Volume 32 Number 6 BioPharm - nanoform.com · BioPharma Services Development SGS Life Science...

The Science & Business of Biopharmaceuticals

BioPharmINTERNATIONAL

June 2019

Volume 32 Number 6

CAN NANOTECH DELIVER BIG DRUG BENEFITS?

www.biopharminternational.com

UPSTREAM PROCESSING

STREAMLINING UPSTREAM

PROCESSING:

A GOOD PLACE TO START

OPERATIONS

MOVING PAT FROM

CONCEPT TO REALITY

PEER-REVIEWED

COMPARING FACILITY LAYOUT

OPTIONS FOR MANAGING

BUSINESS AND OPERATING RISKS

FOR PERSONAL, NON-COMMERCIAL USE

http://www.biopharminternational.com


CONTACT DETAILS:

Eric Dienstbach

303.779.4345

[email protected]

www.bins.properties/bldr-BP

AVAILABLE:BIOPHARMA OPPORTUNITYBiologic Manufacturing Facility - 178,713 gross SF on 20 Acres

5550 Airport Blvd., Boulder, CO 80301

The information contained herein is from sources deemed reliable, but no warranty or representation

is made as to the accuracy thereof and no liability may be imposed. 05/19 RMA

ADDITIONAL INFORMATION:

��7KH�IDFLOLW\�LV�GHVLJQHG�IRU�FHOO�FXOWXUH�SURGXFWLRQ�ZLWK�VLJQL¿�FDQW�

investment recently made in process equipment and upgrading utilities.

• This facility houses drug substance manufacturing

(two 20,000 liter bioreactors), day staging area, quality

control laboratories and central utilities.

• A detached generator building was built in 2000.

• The building is optimally equipped for a user-operator looking to

pursue both research and production under one roof.

��7KH�IDFLOLW\�R��HUV�HDV\�DFFHVV�WR�,��DQG�86�5RXWH��

8QLYHUVLW\�RI�&RORUDGR�LQ�%RXOGHU�DQG�&RORUDGR�6WDWH�8QLYHUVLW\�

in Fort Collins are both within an easy commute to the site.


mailto:[email protected]

http://www.bins.properties/bldr-BP

http://www.binswanger.com/

INTERNATIONAL

BioPharmThe Science & Business of Biopharmaceuticals

© 2019 MultiMedia Healthcare LLC All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical including by photocopy, recording, or information storage and retr ieval without permission in writing from the publisher. Authorization to photocopy items for internal/educational or personal use, or the internal/educational or personal use of specific clients is granted by MultiMedia Healthcare LLC for libraries and other users registered with the Copyright Clearance Center, 222 Rosewood Dr. Danvers, MA 01923, 978-750-8400fa x 978-646-8700 or v is i t h t tp: //w w w.copyr ight .com onl ine. For uses beyond those l is ted above, please direc t your wr i t ten request to Permission Dept. fax 732-647-1104 or email: [email protected].

MultiMedia Healthcare LLC provides cer tain customer contact data (such as customers’ names, addresses, phone numbers, and e-mail addresses) to third parties who wish to promote relevant products, services, and other opportunities that may be of interest to you. If you do not want MultiMedia Healthcare LLC to make your contact information available to third par ties for marketing purposes, simply call toll-free 866-529-2922 between the hours of 7:30 a.m. and 5 p.m. CST and a customer service representative will assist you in removing your name from MultiMedia Healthcare LLC Life Sciences’ lists. Outside the U.S., please phone 218-740-6477.

BioPharm International does not verify any claims or other information appearing in any of the advertisements contained in the publication, and cannot take responsibility for any losses or other damages incurred by readers in reliance of such content.

BioPharm International welcomes unsolicited articles, manuscripts, photographs, illustrations, and other materials but cannot be held responsible for their safekeeping or return.

To subscribe, call toll-free 888-527-7008. Outside the U.S. call 218-740-6477.

EDITORIAL

Editorial Director Rita Peters [email protected]

Senior Editor Agnes M. Shanley [email protected]

Managing Editor Susan Haigney [email protected]

European Editor Felicity Thomas [email protected]

Science Editor Feliza Mirasol [email protected]

Manufacturing Editor Jennifer Markarian [email protected]

Associate Editor Amber Lowry [email protected]

Art Director Dan Ward [email protected]

Contributing Editors Jill Wechsler, Eric Langer, Anurag Rathore, and Cynthia A. Challener, PhD

Correspondent Sean Milmo (Europe, [email protected])

ADVERTISING

Publisher Mike Tracey [email protected]

National Sales Manager Scott Vail [email protected]

European Sales Manager Linda Hewitt [email protected]

European Senior Sales Executive Stephen Cleland [email protected]

C.A.S.T. Data and List Information Michael Kushner [email protected]

Licensing and Reuse of Content: Contact our official partner, Wright’s Media, about available usages, license fees, and award seal artwork at [email protected] for more information. Please note that Wright’s Media is the only authorized company that we’ve partnered with for MultiMedia Healthcare materials.

PRODUCTION

Production Manager Jesse Singer [email protected]

AUDIENCE DEVELOPMENT

Audience Development Christine Shappell [email protected]

Thomas W. Ehardt

PresidentMultiMedia Healthcare LLC

Dave Esola

VP/Managing Director, Pharm/Science Group

MultiMedia Healthcare LLC

K. A. Ajit-SimhPresident, Shiba Associates

Madhavan BuddhaFreelance Consultant

Rory BudihandojoDirector, Quality and EHS Audit

Boehringer-Ingelheim

Edward G. CalamaiManaging Partner

Pharmaceutical Manufacturing

and Compliance Associates, LLC

Suggy S. ChraiPresident and CEO

The Chrai Associates

Leonard J. GorenGlobal Leader, Human Identity

Division, GE Healthcare

Uwe GottschalkVice-President,

Chief Technology Officer,

Pharma/Biotech

Lonza AG

Fiona M. GreerGlobal Director,

BioPharma Services Development

SGS Life Science Services

Rajesh K. GuptaVaccinnologist and Microbiologist

Denny KraichelyAssociate Director

Johnson & Johnson

Stephan O. KrauseDirector of QA Technology

AstraZeneca Biologics

Steven S. KuwaharaPrincipal Consultant

GXP BioTechnology LLC

Eric S. LangerPresident and Managing Partner

BioPlan Associates, Inc.

Howard L. LevinePresident

BioProcess Technology Consultants

Hank LiuHead of Quality Control

Sanofi Pasteur

Herb LutzPrincipal Consulting Engineer

Merck Millipore

Hanns-Christian MahlerHead Drug Product Services

Lonza AG

Jerold MartinIndependent Consultant

Hans-Peter MeyerLecturer, University of Applied Sciences

and Arts Western Switzerland,

Institute of Life Technologies

K. John MorrowPresident, Newport Biotech

David RadspinnerGlobal Head of Sales—Bioproduction

Thermo Fisher Scientific

Tom RansohoffVice-President and Senior Consultant

BioProcess Technology Consultants

Anurag RathoreBiotech CMC Consultant

Faculty Member, Indian Institute of

Technology

Susan J. SchnieppExecutive Vice President of

Post-Approval Pharma

and Distinguished Fellow

Regulatory Compliance Associates, Inc.

Tim SchofieldConsultant

CMC Sciences, LLC

Paula ShadlePrincipal Consultant,

Shadle Consulting

Alexander F. SitoPresident,

BioValidation

Michiel E. UlteePrincipal

Ulteemit BioConsulting

Thomas J. Vanden BoomVP, Biosimilars Pharmaceutical Sciences

Pfizer

Krish VenkatManaging Partner

Anven Research

Steven WalfishPrincipal Scientific Liaison

USP

EDITORIAL ADVISORY BOARDBioPharm International’s Editorial Advisory Board comprises distinguished

specialists involved in the biologic manufacture of therapeutic drugs,

diagnostics, and vaccines. Members serve as a sounding board for the

editors and advise them on biotechnology trends, identify potential

authors, and review manuscripts submitted for publication.



















http://www.copyr


https://auditedmedia.com/

http://www.asbpe.org/about-us/

4 BioPharm International June 2019 www.biopharminternational.com

Table of Contents

BioPharm International integrates the science and business of biopharmaceutical research, development, and manufacturing. We provide practical, peer-reviewed technical solutions to enable biopharmaceutical professionals to perform their jobs more effectively.

BioPharm International is selectively abstracted or indexed in: • Biological Sciences Database (Cambridge Scientifi c Abstracts) • Biotechnology and Bioengineering Database (Cambridge Scientifi c Abstracts) • Biotechnology Citation Index (ISI/Thomson Scientifi c) • Chemical Abstracts (CAS) • Science Citation Index Expanded (ISI/Thomson Scientifi c) • Web of Science (ISI/Thomson Scientifi c)

BioPharm International ISSN 1542-166X (print); ISSN 1939-1862 (digital) is published monthly by MultiMedia Healthcare LLC 325 W. First Street, STE 300 Duluth, MN 55802. Subscription rates: $76 for one year in the United States and Possessions; $103 for one year in Canada and Mexico; all other countries $146 for one year. Single copies (prepaid only): $8 in the United States; $10 all other countries. Back issues, if available: $21 in the United States, $26 all other countries. Add $6.75 per order for shipping and handling. Periodicals postage paid at Duluth, MN 55806, and additional mailing offi ces. Postmaster Please send address changes to BioPharm International, PO Box 6128, Duluth, MN 55806-6128, USA. PUBLICATIONS MAIL AGREEMENT NO. 40612608, Return Undeliverable Canadian Addresses to: IMEX Global Solutions, P. O. Box 25542, London, ON N6C 6B2, CANADA. Canadian GST number: R-124213133RT001. Printed in U.S.A.

FEATURES

DEVELOPMENTTaking TherapeuticAntibodies to the Next LevelFeliza Mirasol

This article explores the challenges and

potential of next-generation therapeutic

antibodies. . . . . . . . . . . . . . . . . . . . . . .14

UPSTREAM PROCESSINGStreamlining Upstream Processing: A Good Place to StartFelicity Thomas

As cost and time pressures within

biopharma are on the rise, innovative

expression systems may offer companies

a good opportunity to streamline

processes early on. . . . . . . . . . . . . . . . .18

DOWNSTREAM PROCESSINGAddressing the Complex Nature of Downstream Processing with QbDSusan Haigney

Quality by design brings both challenges

and benefits to the development of

downstream processes. . . . . . . . . . . . .22

PEER-REVIEWEDComparing Facility Layout Options for Managing Business and Operating RisksMark F. Witcher and Harry Silver

The authors present a risk

analysis of the impact of

various business and operating

risks on three facility layout

strategies. . . . . . . . . . . . . . . . . . . . . . . .26

DATA ANALYTICSFrom Data to InformationAgnes Shanley

Making siloed data accessible

across functions and to contract

partners is the first step to facilitating

continuous improvement and

enabling use of artificial intelligence

in manufacturing. . . . . . . . . . . . . . . . . .33

OPERATIONSMoving PAT from Concept to RealityCynthia A. Challener

The learning curve for process

analytical technology has slowed

widespread adoption. . . . . . . . . . . . . . 37

SUPPLY CHAINOn the Right TrackFelicity Thomas

Proactive approaches that

consider long-term supply chain

security compliance are recommended

to ensure companies stay on the

right track. . . . . . . . . . . . . . . . . . . . . . . .42

COLUMNS AND DEPARTMENTS

FROM THE EDITOR

FDA’s annual manufacturing

report card shows more quality

compliance is needed.

Rita Peters . . . . . . . . . . . . . . . . . . . . . . . . .6

REGULATORY BEAT

CDER’s KASA program seeks

manufacturer data on drug

attributes and risks to inform oversight.

Jill Wechsler . . . . . . . . . . . . . . . . . . . . . . .8

NEW TECHNOLOGY

SHOWCASE . . . . . . . . . . . . . . . . . . . . . .45

AD INDEX . . . . . . . . . . . . . . . . . . . . . . . .45

ASK THE EXPERT

A good working relationship

between sponsor and contractor

will become invaluable when an

OOS occurs.

Susan Schniepp . . . . . . . . . . . . . . . . . . .46

COVER STORY

10 Can NanotechnologyDeliver Big Drug Benefi ts?Research advances have enabled the application of nanotechnology to drug delivery. What does this technology offer in the way of enhancing therapeutic effect?

Cover Design by Dan WardImage: MG - stock.adobe.com



http://www.biopharminternational.com/

USP is the logical choice for residual host cell DNAReference StandardsResidual host cell DNA must be minimized as much as possible during

production of therapeutic proteins. The removal or reduction of host cell

DNA is mandatory for biopharmaceuticals, requiring accurate and sensitive

tests to quantify such impurities and to meet guidelines established by

regulatory agencies.

USP will help you demonstrate removal of residual genomic DNA

throughout the lifecycle of your product by off ering:

• two highly characterized Reference Standards for residual host cell

DNA: CHO genomic DNA and E. coli genomic DNA.

• General Chapter <509> Residual DNA Testing that features:

– a publicly available, validated method to detect residual genomic DNA

– confirmed primer and probe sequences that provide flexibility in

choice of labeling reagents

USP off ers additional Performance Standards – broadly applicable

standards that are used to demonstrate and help ensure methods and

process performance throughout the product lifecycle of a biologic.

Biologics.usp.org/BP1For Reference Standards that you can trust, visit:

Reference Standards are associated with validated qPCR methods

• CHO Genomic DNA RS (catalog #1130710)

• E. coli Genomic DNA RS (catalog #1231557) Now available


https://biologics.usp.org/residual-genomic-dna-reference-standards?utm_campaign=Residual%20host%20cell%20DNA%20Full%20page%20print%20ad&utm_source=Print&utm_medium=BioPharm

https://biologics.usp.org/residual-genomic-dna-reference-standards?utm_campaign=Residual%20host%20cell%20DNA%20Full%20page%20print%20ad&utm_source=Print&utm_medium=BioPharm

6 BioPharm International www.biopharminternational.com June 2019

From the Editor

FDA’s annual

manufacturing

report card shows

more quality

compliance

is needed.

Bio/Pharma Facilities Still Have a Lot to Learn

As schools in the United States close for the summer break, student grades

serve as a measure of how well teachers shared knowledge, how well stu-

dents understood and retained that information, and how the school, as a

whole, performed year over year.

FDA recently issued a report card of the bio/pharma industry’s manufacturing

quality performance. The Report on the State of Pharmaceutical Quality (1), issued

in May 2019 by the Office of Pharmaceutical Quality in FDA, Center for Drug

Evaluation and Research, assessed the ability of pharmaceutical manufacturers to

deliver quality pharmaceutical products to the US market during fiscal year 2018.

The report analyzed product recalls, quality defect reports, drug shortages, and

application state (e.g., submissions, approvals, refuse-to-file, refuse-to-receive, and

complete response letters) as a basis for its analysis.

The report examined manufacturing site data by geographic region, therapeutic

category, application type, and manufacturing sector. FDA issues a site inspection

score—on a scale of 1 to 10 with a higher number indicating greater compliance

with current good manufacturing practices—based on FDA quality inspections

over the past 10 years.

Of the 4676 sites in FDA’s catalog, 42% manufacture “no application” products,

such as over-the-counter products, monograph, unapproved, or homeopathic

products. The remaining 58% of sites manufacture application drug products (e.g.,

new drug application [NDA], abbreviated new drug applications [ANDA], biologic

license application [BLA], etc.) and nearly half (46%) of these sites manufacture

both NDA and ANDA products.

The report noted “volatility” in the site catalog in the past year; the agency

removed from the catalog “a large number” of sites in India, China, and South

Korea in FY2018 because they did not make products for the US market and,

therefore, did not have to be registered with FDA. This indicates “a lack of under-

standing of the registration and listing requirements,” FDA noted in the report.

The agency also reported a 32.8% net increase in the number of packaging and

labeling sites—suggesting an increase in outsourcing of these functions.

Less than 40% of the drugs for the US market are manufactured in the US.

India (12%) and China (11%) are the two largest offshore suppliers. FDA also

noted that a small number of sites are responsible for manufacturing a large

number of listed products; the number of products manufactured at a site is a risk

factor used in prioritizing the need for surveillance inspections. In the US, three

sites—two of which make homeopathic products—account for 9.5% of all prod-

ucts listed by all US sites. The number of listed products manufactured by the top

three sites in China (11.2%) and India (12%) are even higher.

Inspections and gradingIn FY2018, FDA conducted 1346 drug quality inspections, covering less than

one-third of sites in its catalog. More than half of the inspections were outside

the US. The average inspection score of 7.5 for FY2018 was down slightly from

FY2017 (7.7). Sites in the European Union (7.9) and the US (7.7) scored higher

than average; sites in China (7.0), India (7.0), and the rest of the world (7.2)

were lower than average. Statistical differences were also noted in application

areas, with sterile non- application products as one of the lowest performing.

FDA noted “… some trends highlight opportunities for increased outreach

to, surveillance of, and enforcement of certain markets,” indicating that for

regulated drug manufacturing, school is never out.

Reference1. FDA, Report on the State of Pharmaceutical Quality, May 13, 2019. X

Rita Peters is the

editorial director of

BioPharm International.



Quality goes up.

Headaches go down.

Quality isn't just a box you check. It’s not limited to a process or even a department. It’s the

ultimate differentiator. The MasterControl Platform helps you digitize, automate and connect critical

processes, documents and data so you can improve quality across your entire product life cycle.

Explore how quality changes everything at www.mastercontrol.com


http://www.mastercontrol.com

https://www.mastercontrol.com/


Regulatory Beat

Vis

ion

so

fAm

eri

ca

/Jo

e S

oh

m/G

ett

y I

ma

ge

s

As part of its ongoing efforts to ensure

the availability of high-quality medi-

cines, FDA’s Center for Drug Evaluation

and Research (CDER) is rolling out a new sys-

tem to enhance the evaluation of prescription

drug attributes, risks, and control strategies. The

Knowledge-aided Assessment and Structured

Application (KASA) initiative aims to improve

the efficiency, consistency, and objectivity

of regulatory quality assessment by collect-

ing structured data on drug substance, prod-

uct design, and manufacturing process to

better assess inherent risks and how they are

controlled. CDER’s Office of Pharmaceutical

Quality (OPQ) is piloting the program first for

abbreviated new drug applications (ANDAs) for

generics, with the aim of rolling out the system

to generic solid oral dosage forms by year-end.

Next will come generic liquids and injectables,

followed by new drugs and biologics.

With more ANDAs and new drug applica-

tions (NDAs) filed each year, many involv-

ing complex therapies, and increasingly tight

assessment time frames for approval set by

user fee programs, CDER officials are looking

for ways to evaluate submissions more expe-

ditiously and effectively. This new

approach asks manufacturers to file

structured applications that present

key data on product attributes, as

opposed to lengthy, text-based nar-

ratives. The aim is for OPQ staffers

to perform computer-aided analyses

that support benefit/risk assessments

for comparison across products and

facilities. Under development for

almost two years, the KASA initia-

tive became more visible when it was

discussed publicly and gained unani-

mous support at the September 2018

meeting of FDA’s Pharmaceutical

Science & Clinical Pharmacology Advisory

Committee.

CDER and OPQ leaders presented more

detailed information on KASA at the April 2019

PQRI/FDA conference on Advancing Product

Quality in Rockville, MD (1). KASA aims to pro-

vide a structured assessment of an application

that summarizes key information and “mini-

mizes text-based narratives,” explained OPQ

Deputy Director Lawrence Yu. Advances in infor-

mation technology not only generate more infor-

mation on key quality attributes, Yu pointed out,

but also allow for a faster, more complete assess-

ment. He directed manufacturers to an article

outlining the KASA program in the International

Journal Of Pharmaceutics: X for further informa-

tion on the program and its approach (2).

Similarly, at the April 2019 CMC Workshop

sponsored by the Drug Information Association

(DIA), Geoffrey Wu, associate director of OPQ’s

Office of Lifecycle Drug Products (OLDP),

described how the KASA initiative will capture

and manage knowledge of drug product quality

to establish a product risk control strategy for

lifecycle management. This approach will avoid

inconsistent application of quality standards

and help prevent shortages and quality fail-

ures of marketed drugs. KASA also will assess

FDA Advances New Approach to Drug Quality Assessment CDER’s KASA program seeks manufacturer data on drug attributes and risks to inform oversight.

Jill Wechsler is

BioPharm International’s

Washington editor,

[email protected].

The KASA initiative

aims to improve the

efficiency, consistency, and

objectivity of regulatory

quality assessment.




June 2019 www.biopharminternational.com BioPharm International 9

Regulatory Beat

manufacturing risks and controls

in order to “f lag the potential

need for a pre-approval inspec-

tion based on multiple factors and

complexities using standardized

risk thresholds,” Wu noted. This

will involve examining the con-

trol strategy for the manufacturing

facility, including site inspection

history, based on a standardized

assessment of r isks compared

across products and facilities.

MORE STRUCTURED ASSESSMENTSThe modern drug assessment sys-

tem under KASA will build on

algorithms of risk and support

computer-aided analysis for a struc-

tured assessment of an application.

The process begins with an objec-

tive evaluation of risk that consid-

ers key critical quality attributes,

enabling OPQ staff to then focus

on more risky products. The anal-

ysis considers the severity of pos-

sible harms and the detectability of

future failures to be able to compare

risks across products and determine

if attributes are within or outside

acceptable ranges. With such infor-

mation, CDER still may approve a

risky product, but with a recognition

of the need for greater oversight to

control for possible future problems.

In making the case for KASA at

the PQRI meeting, OLDP Director

Susan Rosencrance observed that

applications for new drugs and

generics composed of unstructured

text can be a hindrance to an effi-

cient agency assessment of product

quality. Too often, she said, the

important information on how an

applicant controls risk “is lost in

hundreds of pages of text.” This

may encourage a reviewer’s quality

assessment to be more subjective,

leading to inconsistent decisions

by the agency.

Drug applications that pres-

ent information in prose require

reviewers to do “a lot of hunt-

ing and pecking” to pull out

key data, added Mary Ann Slack,

director of CDER’s Off ice of

Strategic Programs. To move for-

ward, FDA plans to develop and

test electronic data standards for

submitting product quality and

chemistry, manufacturing, and

controls (CMC) data to the agency,

Slack explained. This will be

described in draft guidance slated

for publication by March 2020 to

further explain how future appli-

cations should present data files

that can be entered into FDA’s drug

data system to check ranges and

areas to review more closely.

KASA is part of broader CDER

efforts to modernize its drug reg-

ulatory program. This includes

reorganizing the Office of New

Drugs, developing new IT plat-

forms and applications, establish-

ing quality metrics, and building

the emerging technology program

to promote new drug design and

manufacturing strategies. More

consistent and objective regula-

tory assessments under KASA fits

these broader goals by helping FDA

achieve more first-cycle approv-

als for manufacturers and more

affordable and accessible medi-

cines for patients.

REFERENCES1. PQRI, 4th FDA/PQRI Conference on

Advancing Product Quality, April 2019,

https://pqri.org/4th-fda-pqri-

conference-on-advancing-product-

quality-presentations/

2. L. X. Yu et al., International Journal of

Pharmaceutics: X, 1 (December 2019),

www.sciencedirect.com/science/

article/pii/S2590156719300246 ◆

FDA Publishes Guidance on Therapeutic Protein Biosimilars

On May 21, 2019, FDA published guidance (1) on the design and evaluation of comparative analytical studies used to support the biosimilarity of a proposed therapeutic protein product to a reference product licensed under section 351(a) of the Public Health Service Act (PHS Act). The guidance also offers recommendations on the scientific and technical information for the chemistry, manufacturing, and controls (CMC) portion of a marketing application for a proposed product submitted under section 351(k) of the PHS Act.

Among an overview of the PHS Act and the Biologics

Price Competition and Innovation Act of 2009 (BPCI Act),

the guidance specifically discusses expression systems,

manufacturing processes, physicochemical properties,

functional activities, target binding, impurities, reference

products and standards, finished drug products, and

stability. Considerations addressed for a comparative

analytical assessment include reference and biosimilar

products and data analysis.

The guidance is part of a series of documents

to facilitate the implementation of the BPCI Act. Other

guidance documents address scientific considerations,

biosimilar development , c l in ical pharmacology

data, labeling of biosimilars, and demonstrating

interchangeability.

Reference

1. FDA, Development of Therapeutic Protein Biosimilars:

Comparative Analytical Assessment and Other Quality-Related

Considerations, Guidance for Industry (FDA, May 2019).

—The editors of BioPharm International



https://pqri.org/4th-fda-pqri-conference-on-advancing-product-quality-presentations/

http://www.sciencedirect.com/science/


Drug Delivery Systems

Can NanotechnologyDeliver Big Drug Benefi ts?Research advances have enabled the application of

nanotechnology to drug delivery. What does this technology offer in the way of enhancing therapeutic effect?

FELIZA MIRASOL

Bioavailability of a drug substance is a consistent challenge

in the development of both small-molecule and large-

molecule therapeutics. The ability to ensure or enhance

the therapeutic effect of a drug product has led to various

innovations in drug delivery technology. Nanotechnology is one

innovation under exploration as a potential drug delivery vehicle.

Nanoparticles hold significant potential as an effective

drug-delivery system. They typically range in sizes less than

100 nm in at least one dimension and can consist of differ-

ent biodegradable substances, such as natural or synthetic

polymers, lipids, or metals. According to a study by S.S. Suri

et al., nanoparticles are taken up by cells “more efficiently

than larger micromolecules and, therefore, could be used as

effective transport and delivery systems” (1). By incorporating

nanoparticles, drugs can either be integrated into the particle

matrix or be attached to the particle surface.

Though a relatively newer science, “nanomedicine” and

nano-delivery systems are nevertheless rapidly developing.

Nanotechnology offers multiple benefits in treating chronic

human diseases with its ability to provide site-specific and

target-oriented delivery of precise medicines. There have

recently been a number of applications of nanomedicine (e.g.,

chemotherapeutic agents, biological agents, immunothera-

peutic agents) in treating various diseases (2).

Today, companies such as N4 Pharma, a UK-based phar-

maceutical company specializing in a novel silica nanopar-

ticle delivery system for vaccines and therapeutics, and

Nanoform, a Finland-based company that offers services in

nanotechnology and drug particle engineering, are push-

ing forward with their respective technology develop-

ment using nanotechnology in drug delivery applications.

Nigel Theobald, founder and CEO of N4 Pharma, and

Gonçalo Rebelo de Andrade, chief of business operations at

Nanoform, shared with BioPharm International the inroads

these companies are making and how nanotechnology can

enhance the therapeutic effects of biologic-based drugs as

well as traditional small-molecule drugs.

MG

- s

tock

.ad

ob

e.c

om



Take advantage of unparalleled opportunities to hear from and engage with

regulatory and industry experts at the 2019 PDA/FDA Joint Regulatory Conference!

Stay up to date with the latest industry and regulatory advancements at this exceptional Conference!

Find out how the continuing evolution of innovative manufacturing capabilities will affect quality, compliance, and regulatory

paradigms. Over two and a half days, the best in the industry will offer their perspectives on these topics and more:

• Combination products and

connected care applications

• Effective internal and

external audits

• Designing aseptic processes

to reduce quality risk

• Data integrity remediation and an

update on the associated PDA

Technical Report

• Evolving approaches to quality

management systems

• Improving deviation and failure

investigations

• Strategies for continuous

improvement of facilities and

equipment

Other Conference highlights include:

• The always popular Center Updates

• NEW TIME: Lunch with the Regulators session

• Networking Opportunities

• Exhibition featuring product and service solutions to improve your company’s processes

Join nearly 1,000 of your industry peers at this “can’t-miss” event!

To learn more and register, visit pda.org/2019PDAFDA

pda.org/2019PDAFDA

SEPTEMBER 16-18 | WASHINGTON, DC EXHIBITION: SEPT. 16-17

#2019PDAFDA

2019 PDA/FDAJoint Regulatory

ConferenceManufacturing Innovation, Quality,

and Compliance:

Achieving 20/20 Vision

Registerby July 30

and save upto $600!


https://www.pda.org/global-event-calendar/event-detail/2019-pda-fda-joint-regulatory-conference



https://www.fda.gov/



MAKING INROADSBioPharm: What is nanotechnology,

and how is it suited to be a platform or

vehicle for drug delivery?

Theobald (N4 Pharma): People

started talking about nanotechnology in

the context of drug delivery more than 10

years ago. However, back then it was all

about legacy drug delivery technology that

happened to be in the nano-size range—

generally accepted to be 1 nm to 1000 nm

—being applied to improve the bioavail-

ability or negate toxicity challenges with

existing small-molecule drugs. Liposomes

were the hot topic, and several drugs came

to market in this new dosage form.

Fast forward to today, and the discus-

sion—as well as the technology and tar-

gets—have moved on considerably, with

the majority of activity concentrated on

developing improved vaccines and cancer

therapeutics using DNA, RNA, or other

large-molecule approaches.

A n d r a d e ( N a n o f o r m ) :

Nanotechnology is the science that

manipulates, generates, and utilizes sub-

micron sized materials. In the pharmaceu-

tical space, nanotechnology is associated

with the manipulation and generation

of excipients. This includes silicon-based

nanoparticles, lipid nanoparticles, and

liposomes, which are used as formulation

adjuvants and dissolution enhancers of

drug substances. Through the manipula-

tion and generation of API nanoparticles,

drug molecules can become more soluble,

thus enabling a faster onset, a larger thera-

peutic window, and reduced side effects.

In recent years there have also been ini-

tiatives to generate intelligent biomaterials

(e.g., with sensors and nanotech circuits)

that can be used for sustained release, add-

ing to the already long line of existing

enhanced performance biomaterials (e.g.,

biomaterials with silver nitrate nanopar-

ticle deposition at the surface for medical

device and implant infection reduction).

BioPharm: What is the biggest hur-

dle to overcome?

Andrade (Nanoform): While devel-

oping any new and innovative technology,

scientists and companies alike are faced

with not only the uncertainty of the success

of its delivery platform (technology devel-

opment risk), but also the adoption barrier

associated with a lack of previous experi-

ence with the technology (market risk). In

addition, given the nature of drug delivery

within the pharmaceutical industry, there

are safety and toxicology requirements that

scientists and companies will need to com-

ply with (regulatory risk) to obtain market

approval.

Theobald (N4 Pharma): At present,

our work is specific to vaccines and cancer

therapeutics, and in this scenario, the drug

delivery system must cope with the spe-

cific challenges of delivering nucleic acids

(DNA/RNA).

A DNA/RNA drug may have rela-

tively poor immunogenicity, and they are

unstable in vivo. So, the goal in the body

is to protect the messenger RNA/plasmid

DNA (mRNA/pDNA) from the immune

system and deliver it to the site of action

before releasing it to stimulate an immune

response, whereby the body’s own systems

either attack the target tumor or produce

enough antibodies against it.

If you’ve got a DNA/RNA-based

active, therefore, you’re going to have to

develop it together with a delivery system.

In fact, there are a range of technologies

that can be considered, such as drug-pro-

tein conjugates and virus-like vectors, but

lipid nanoparticles (LNPs) have emerged

as the most common approach to date.

LNPs meet many of the criteria men-

tioned above for a good drug delivery

system. However, they exhibit some

well-known limitations, most nota-

bly: stimulating the release of systemic

inflammatory cytokines; accumulation in

the liver and spleen, with resulting pos-

sibility of toxicity; low drug payload for

hydrophilic molecules; drug expulsion;

and reticuloendothelial system (RES)

clearance for systemic drug delivery (3).

Importantly, LNPs also suffer from sub-

optimal cellular penetration; it is interesting

to note that currently, of 23 cancer vaccines

in Phase II/III trials, 18 showed low clini-

cal effect, probably due to insufficient pre-

sentation of the tumor-associated antigens.

REGULATORY CONSIDERATIONSBioPharm: What regulatory hurdles

have to be overcome, and what kind of

guidance does the industry have—or

lack—from regulatory authorities?

Theobald (N4 Pharma): Neither

FDA nor the European Medicines

Agency (EMA) place specific barriers on

a company using nanotechnology as part

of its drug delivery modality, but at the

same time they have not yet come to a

firm view on its use because it is so novel

and varied. FDA—in draft guidance for

industry, published late in 2017 (4)—pro-

vides a risk-based framework that covers

safety; preclinical studies such as absorp-

tion, distribution, metabolism, excretion,

and toxicity; and clinical trials.

EMA’s position, as presented in their

Reflection Paper on Nanotechnology-

Based Medicinal Products for Human Use

(5), is also clear: ‘As for any medicinal prod-

uct, the [European Union] EU-competent

authorities will evaluate any application

to place a nanomedicinal product on the

market, utilising established principles of

benefit/risk analysis, rather than solely on

the basis of the technology per se.’

In practice, both regulatory agencies are

pleased to engage with a company early in

the drug development process to ensure

that any specific nanotechnology aspects

are appropriately dealt with ahead of an

application.

Andrade (Nanoform): As with

every other technology that is incorpo-

rated into a drug product, the use of nano-

technology needs to provide sufficient

evidence of its safety, tolerability, and the

control of its manufacturability. In the

spirit of collaboration with the industry

that the regulatory authorities have long

demonstrated, FDA’s nanomaterials guid-

ance provides additional information to

the industry as to how the agency will

review an application that incorporates

nanotechnology into the developed drug

product.

THERAPEUTIC ADVANTAGEBioPharm: What therapeutic advantage

does nanotechology offer?



www.biopharminternational.com June 2019 BioPharm International 13


A n d r a d e ( N a n o f o r m ) :

Nanotechnology has been traditionally

associated with the pursuit of improved

solubility and dissolution for poorly solu-

ble small-molecule drugs and the genera-

tion of sustained drug release formulations.

Recent advances in the generation of

nanoparticles, however, have demon-

strated increased biologic membrane

permeability associated with nanopar-

ticles. Greater permeability enables deeper

penetration in the tumor microenviron-

ment, leading to its increased application

in oncology and the generation of more

effective drug product formulations.

Nanotechnology-driven drug products

have shown to have a faster onset in terms

of therapeutic action, due to the increased

solubility of the nanosized API. It offers

a potential reduction of the daily dose

required for a therapeutic effect, while also

enabling a decrease in side effects associ-

ated with the drug uptake.

Theobald (N4 Pharma): In gen-

eral, everyone developing drug vaccines

consisting of nucleic acids is looking to

achieve some or all of the following ben-

efits from delivery systems:

• Protection of the drug substance from

early or rapid degradation in the body

• Preferential delivery to the target site

of action

• A combination of high loading

capacity, controlled release with

extended half-life, no leakage, and no

interference with the stability of the

encapsulated product.

In addition, good biocompatibility, low

toxicity, and biodegradability, as well as

a clear understanding of the mode of

action of the delivery system, are desir-

able factors. To achieve this, many believe

that nanoparticle delivery is critical to

enabling these drugs to be used effec-

tively in a therapeutic setting.

TECHNOLOGY IN DEVELOPMENTBioPharm: Can you briefly walk us

through your brand of nanotechology and

where in the manufacturing process it is

implemented?

Theobald (N4 Pharma): Our

approach has been different and our

technology—called Nuvec—is a delivery

system with differentiated physical and

structural properties specifically adapted

to carry mRNA, pDNA, and other ther-

apeutic proteins. Nuvec nanoparticles

are hollow silica spheres covered in thin

silica structures that are functionalised

with polyethyleneimine (PEI) to enhance

binding of macromolecules. The nanopar-

ticles are 180 nm but can be made avail-

able from 120 nm to 500 nm in size. Its

unique ‘spikey’ surface traps and protects

the looped structure of nucleic acids.

Nuvec has been designed to deliver

the cargo directly into the cells, and its

properties have the potential to over-

come many of the challenges of other

approaches. The technology works

by simply and effectively trapping and

protecting nucleic acid (such as mRNA/

pDNA) as it travels to the cells. It does

not totally encapsulate the DNA or RNA,

but rather binds and protects enough to

deliver good transfection. The high sur-

face area of the nanoparticle, due to the

spikes, allows for high levels of material to

be loaded onto the particle.

Once inside the cell, the cargo load

is released to activate the immune sys-

tem. Nuvec is also a natural adjuvant,

so it attracts a large number of innate

immune cells, which, in turn, leads to

more activation of the adaptive immune

system (T and B cells), thus increasing

the level of immune response against the

target cancer cells.

The Nuvec system offers the advantage

of not posing unwanted systemic side-

effects. Our data show that the trapped

drug remains at the site of injection, doesn’t

produce unwanted inflammatory responses,

and, very importantly, doesn’t track to the

liver. Nuvec is provided as PEI-loaded

nanoparticles that can then have the rel-

evant DNA or mRNA loaded onto them

via a simple mixing process. The final

drug product will involve the combination

of the Nuvec particle with the DNA or

mRNA itself. Nuvec is an intermediate

step in the final drug product manufacture.

Andrade (Nanoform): At

Nanoform, we have developed a tech-

nology called Controlled Expansion of

Supercritical Solutions (CESS) to engi-

neer API particles to the nanosized scale

that will give failed drug candidates a

second chance and enable more success-

ful drug product development. CESS

elevates particle engineering, and we

focus on the generation of crystalline

nanoparticles, typically with a Dv50

(i.e., median volume distribution) below

200 nm, directly from solution and with

a high-yield (over 90%). We take any

API and study its physical and chemical

properties to define the process param-

eters to apply CESS to the molecules for

which we want to generate nanoparticles.

We start by preparing a suspension in

carbon dioxide, turning it into a solu-

tion, and then controlling the nucleation

step by controlled pressure and tempera-

ture drops that are coupled to a final

atomization step. The process is used

to obtain the crystalline nanoparticle

dry powder. As it is a recrystallization

step, Nanoform’s technology is part of

drug-substance manufacturing and can

seamlessly be integrated into any drug

product development supply chain. As

Nanoform’s technology does not require

excipients or surfactants, the free-flowing

nanoparticles generated are compat-

ible with any drug product development

strategy. We anticipate that our work

will double the number of molecules that

enter the market.

REFERENCES1. S. S. Suri, H. Fenniri, and B. Sigh, J

Occup Med Toxicol. 2 (16) (2007).2. J. K. Patra et al., Journal of

Nanobiotechnology 16 (71) (2018).3. G. Parisa and M. Soliman, Research in

Pharmaceutical Sciences 13 (4) (2018).4. FDA, Draft Guidance for Industry,

Drug Products, Including Biological Products, that Contain Nanomaterials (Rockville, MD, December 2017).

5. EMA, Reflection Paper on Nanotechnology-Based Medicinal Products for Human Use, June 2006, www.ema.europa.eu/en/documents/regulatory-procedural-guideline/reflection-paper-nanotechnology-based-medicinal-products-human-use_en.pdf.◆


http://www.ema.europa.eu/en/documents/



Development

Taking TherapeuticAntibodies to the Next Level

This article explores the challenges and potential of next-generation therapeutic antibodies.

FELIZA MIRASOL

Monoclonal antibodies (mAbs) are considered the

standard therapy in the biologics industry follow-

ing decades of research, development, manufacturing

optimization, and commercial success. However, they face

limitations to their long-term efficacy because they can eventu-

ally encounter resistance, such as when a tumor evades immune

control (1). Fortunately, advances in protein engineering tech-

nology have led to the development of alternative antibody

forms, or next-generation antibodies, that may supersede the

limitations of mAbs. At the forefront of a new wave of next-gen

antibodies are bispecific antibodies, which are capable of target-

ing multiple antigens as a single agent. Bispecific antibodies

can directly target immune cells to a tumor, which suggests that

they can significantly reduce drug resistance and severe adverse

side effects commonly experienced with other cancer therapies,

including mAbs (1).

ROAD TO NEXT-GEN ANTIBODIESOver the past 20 years, antibody therapeutics have grown from

nothing to a $120-billion market that is the fastest growing sec-

tor of therapeutics, says Carl Hansen, PhD, CEO and president

of AbCellera, a Canadian biotech company specializing in next-

generation therapeutic antibodies, and professor at the University

of British Columbia, Vancouver, Canada. The biologics industry

has since matured and has grown increasingly more competitive,

driving a need for access to new target spaces and for new tech-

nologies that provide a competitive advantage, Hansen observes.

“On the one hand, the industry is moving towards target

classes that have previously been inaccessible. At the same time,

the competition amongst biotechs driving new antibody thera-

peutics to market has intensified. These market dynamics have

placed a premium on high-end discovery technologies capable

of finding rare antibodies, as well as access to new sources of

antibody diversity that are suited to each specific problem,”

says Hansen.

For example, he notes, antibody discovery from camelids pro-

vides a means to generate high-affinity single-chain antibodies

that can access small epitopes. There is also a trend toward the

creation of formats in which a single molecule can engage two

(bi-specific) or more (multi-specific) targets. Numerous bispecific

formats have been described over the years; however, many of

these have encountered challenges in manufacturing. More Ch

rist

op

h B

urg

ste

dt

- S

tock

.Ad

ob

e.c

om



Let Cygnus Technologies

support your bioprocess

impurity analysis — so you

can stay focused on

product-related analytics!

cygnustechnologies.com

© 2018 Cygnus Technologies. All rights reserved.

For research use only. Not intended for aniŵĂů�Žƌ�ŚƵŵĂŶ�ƚŚĞƌĂƉĞƵƟĐ�Žƌ�ĚŝĂŐŶŽƐƟĐ�ƵƐĞ�

Outsource to the Experts

Our assay kits provide the specificity and sensitivity to

detect impurities with reproducibility that supports

regulatory compliance.

Assay Kits

• Host Cell Protein ELISAs to detect and quantify HCPs from

numerous bioproduction cell lines

• Protein A ELISAs to detect Protein A leachates from leading

Protein A chromatography resins

• Bioprocess Impurity Assays to detect BSA, HSA, Transferrin,

and Insulin

• Host Cell DNA Extraction and Detection Kits

Our advanced orthogonal analysis services identify impurities

to help optimize downstream purification processes.

Contract Services

• Process-Specific Antibody and Assay Development

• Antibody Coverage Analysis

• Antibody Affinity Extraction (AAE)

• Comprehensive Assay Qualification

• HCP Analysis by Mass Spectrometry

Trust your assays. Trust your results.


https://www.cygnustechnologies.com/



Development

recently, these manufacturing challenges

have been solved using protein engi-

neering methods, and several bispecific

molecules have advanced into the clinic,

including immunoglobulin G (IgG)-like

formats and nanobody molecules, which

are truncated single-chain antibodies. The

latter can be linked together to create

constructs that are both simple to manu-

facture and that are capable of targeting

more than one epitope or drug target at

once, Hansen explains.

“Alternative scaffolds are a novel class

of biologic molecules that have been spe-

cifically developed to address identified

shortcomings of mAbs,” adds Dr. Fredrik

Frejd, chief scientific officer of Affibody,

a Swedish biotech company specializ-

ing in next-generation biopharmaceuti-

cals. “Alternative scaffolds are the focus of

companies such as Affibody, Molecular

Partners, and Pieris, and they feature on

par molecular diversity and ability to bind

with high affinity in a structure that is

often better and very different from mAbs.”

Alternative (aka, protein) scaffolds,

which are derived from non-immuno-

globulin proteins endowed with novel

binding sites (2), are used to generate

novel binding proteins via combinatorial

engineering. They have recently emerged

as a compelling alternative to natural or

recombinant antibodies. The concept of

this scaffold requires an “extraordinary

stable protein architecture tolerating mul-

tiple substitutions or insertions at the pri-

mary structural level” (3).

Affibody has developed alternative-

scaffold molecules, called Affibody mol-

ecules, that have shown substantial clinical

usefulness in oncology and inflammation

indications. The company currently has

ongoing clinical trials with three different

Affibody molecules in Phase II/Phase III

for breast cancer imaging, Phase II for

psoriasis, and Phase I for autoimmune

diseases, respectively.

THERAPEUTIC POTENTIALEmerging antibody formats provide a

variety of advantages, Hansen comments.

Bispecific antibodies, for example, provide

the ability to modulate multiple targets in

a single molecule, to direct cell-cell inter-

actions (T cell engagers), to increase target

engagement on multiple epitopes, and to

increase therapeutic windows by selec-

tively targeting tissues or cell types.

Researchers have been able to take the

modular architecture of antibodies and

create more than 60 different bispecific

antibody formats that vary in molecu-

lar weight, number of antigen-binding

sites, spatial relationship between differ-

ent binding sites, valency for each anti-

gen, ability to support secondary immune

functions, and pharmacokinetic half-life,

according to a study by C. Spiess et al. (4).

Having these diverse formats allows for

tailoring the design of bispecifics to match

a proposed mechanism of action and to

serve an intended clinical application.

The Affibody molecules, meanwhile,

offer therapeutic potential via their high

molecular diversity and high stability

as well as by demonstrating high affin-

ity—down to femtomolar affinity—when

binding to targets. “Higher subcutane-

ous doses due to smaller molecular size

translate to greater clinical efficacy than

antibodies, and the smaller size results in

better tissue penetration and access to the

disease target,” says Frejd.

Alternative scaffolds offer improved

manufacturability and can facilitate new

functional combinations, which is likely

to enable unique therapeutic modes of

action that can yield promising therapeu-

tics, such as biobetters (2). Affibody mol-

ecules, specifically, can be manufactured

with predictable processes at low cost and

offer engineering options not accessible

for antibodies, according to Frejd.

CHALLENGES TO DEVELOPMENTNext-gen therapeutic antibodies face

many challenges, and bispecific antibody

challenges in particular include the engi-

neering, development, and manufacture

of the molecules, says Hansen. “Much

of the work on bispecifics has focused

on solving the manufacturing problem

of producing complex molecules with

a single cell line with good purity and

yield,” he comments.

“AbCellera’s platform is displacing

discovery using traditional hybridoma

or display approaches, two technologies

that have changed little over the past

two decades. Our microfluidic platform

allows the direct assessment of antibod-

ies produced by a single cell in hours and

can be applied on a massively parallel

scale to screen more than a million sin-

gle cells per day. As compared to hybrid-

oma methods, our process completely

bypasses the need for a fusion step

where the large majority of antibody

leads are lost, thereby allowing an ultra-

deep search of natural immune systems.

By unlocking the full diversity of natural

immune responses, we can produce large

panels of naturally derived antibodies,

which generally have superior potency,

specificity, and developability as com-

pared to those obtained from synthetic

display libraries,” Hansen adds.

In comparison, Affibody molecules

offer biparatopic and multispecific con-

structs that can be generated at a fraction

of the size and cost of an antibody, which

allows for a switch from intravenous-

infusion dosing regimes conducted in the

clinic to a more convenient subcutaneous

self-administration at home. “Typically,

the production is scalable and predictable,

and as the building blocks in the bi/multi

specific constructs are synthetic, there are

fewer surprises in the generation of the

molecular formats. While two binding

domains remain a limit for many antibody

formats, tri- and multispecific constructs

are routine with Affibody molecules,”

Frejd states.

REFERENCES1. A. Thakur et al., Blood Reviews

32 (4) 339–347 (2018).2. M. Gebauer and A. Skerra,

“Alternative Protein Scaffolds as Novel Biotherapeutics,” in Biobetters, A. Rosenberg and B. Demeule, Eds. (Springer, New York, NY, 2015), pp. 221–268.

3. P.A. Nygren and A. Skerra, J Immunol Methods. 290 (1–2) 3–28 (2004).

4. C. Spiess et al., Molecular Immunology 67 (2A) 95–106 (2015). ◆



2019 PDA EUROPE

BioManufacturing

3-4 SEPTEMBER 2019

MUNICH, GERMANYEXHIBITION: 3-4 SEPTEMBER

IG MEETINGS 2+5 SEPTEMBER

TRAINING: 5-6 SEPTEMBER

REGISTER BEFORE 7 JULY AND SAVE UP TO €200!

pda.org/EU/Bio2019



https://www.pda.org/global-event-calendar/event-detail/biomanufacturing-conference


Upstream Processing

Streamlining Upstream Processing: A Good Place to Start

As cost and time pressures within biopharma are on the rise, innovative expression systems may offer companies a

good opportunity to streamline processes early on.

FELICITY THOMAS

It is well-documented that biopharma companies are under

increasing pressure to reduce timelines and costs associated

with bringing a new biologic medicine to market. While

some efforts to improve time and cost efficiencies have been

made through single-use systems and novel production

methods, such as continuous processing, there may be over-

looked potential in innovative highly productive expression

systems that could aid in the ultimate goal of bringing safe,

effective biotherapies to market quicker and cheaper.

As reported by Allied Market Research, the global bio-

pharmaceuticals market is anticipated to experience sig-

nificant growth over the coming years, potentially reaching

more than $500 billion by the year 2025 (1), with mono-

clonal antibodies (mAbs) expected to maintain dominance

as the main type of product in commercial development. In

terms of expression systems, mammalian-based expression

systems (human-like) are used for most biologics, particu-

larly for mAb bioprocesses, yet these are also attributed with

relative high cost and low efficiency.

“Essentially, there are two key challenges currently fac-

ing the biopharma industry,” says Abhijeet Kohli, product

manager at Thermo Fisher Scientific. “When it comes to

traditional mAb processes, overall timelines are constantly

being challenged and there are continued calls for faster com-

mercialization. Here, the traditional processing methods the

industry follows are proving to be something of a bottleneck.”

The second challenge for Kohli relates to the new types

of biologics that are entering the pipeline. “The bispecific

and trispecific molecules that are increasingly the focus of

immuno-oncology efforts presents a further challenge for

biopharma,” he notes. “These molecules are much more

complex than traditional biologics and consequently have

lower titers, so there is a lot of room to optimize manufac-

turability, reproducibility, and stability.”

CURRENT SYSTEMS: BENEFITS AND LIMITATIONSThe current “work horse” in expression systems for biopharma

is the Chinese hamster ovary (CHO) mammalian cell line, pe

shko

va -

Sto

ck.A

do

be

.co

m




Upstream Processing

confirms Michael A. Cunningham, asso-

ciate director, Upstream Manufacturing

Sciences and Technology (MSAT),

Life Sciences—Process Solutions,

MilliporeSigma. “These expression sys-

tems most commonly rely on antibiotic

or metabolic selection mechanisms to

generate high-expressing cell clones.”

Mark Emalfarb, chief executive officer

of Dyadic International, emphasizes that

there are limitations on specific expres-

sion needs encountered with all cell lines.

“The greatest disadvantage of CHO, for

example, is its low natural productivity

and high cost of drug development on a

gram-per-liter basis production,” he says.

“CHO also has a long production time

line—41–54 days from pre-inoculum to

production bioreactor and 14–21 days

for fermentation process with complex

expensive cell media and buffer require-

ments for cell viability. All this leads to

an expensive cost of goods sold (COGS).”

Additionally, Emalfarb notes that

with CHO cell lines there is a need

for expensive virus inactivation, which

must adhere to strict regulatory require-

ments. “Mammalian cells may harbor or

become infected by viruses which could

render all the previous work of no value,

or even destroy the manufacturing facil-

ity’s value,” adds Terence Ryan, chief

scientific officer of iBio.

A further potential disadvantage of con-

ventional mammalian cell lines may present

itself in the field of next-generation medi-

cines, such as bi/multi-specific antibodies

as well as gene and cell therapies, clarifies

Dr. Fay Saunders, head of upstream mam-

malian cell culture, process development,

at FUJIFILM Diosynth Biotechnologies,

UK site. “Mammalian cells are still limited

in their ability to be able to express more

complex, non-natural ‘designed’ molecules.”

Yet, CHO and other mammalian

cell lines are capable of producing large,

complex proteins with post-translational

modifications (PTMs), which are similar

to those produced in humans, Emalfarb

stresses.

In addition to mammalian/CHO cell

lines, bacterial, insect, and yeast systems,

which according to Dr. Nicholas Holton,

R&D manager at Leaf Expression Systems,

all dominate the landscape of biologics

production. “The use of plants for biologics

production (plant molecular farming) has

been around as a nascent field for many

years but has historically been held back by

significant underfunding as the industry

instead focused on improving the safety

profiles and yields of conventional systems,”

he says. “However, now that plant expres-

sion technology has finally matured and

proven its commercial viability, it is increas-

ingly being recognized as a valid com-

mercially viable manufacturing option for

diagnostic and therapeutic products.”

Ryan also notes that plants can carry

out most of the post-translational modi-

fications exhibited by mammalian cells,

and any additional mammalian-specific

factors necessary for maturation of a bio-

logic can be added with additional vectors.

“Plants do not naturally exactly recapitu-

late human glycosylation (neither do

rodent cells like CHO or myeloma), but

this is generally not an issue, and modified

plants with more human glycosylation

capabilities can serve as hosts, and mAbs

produced in plants have been shown to

have more potency in antibody-depen-

dent cell-mediated cytotoxicity (ADCC)

assays than those made in CHO,” he

says. “Using stably-transformed plant

cells (Protalix) has some of the time

issues of mammalian cells due to the need

to find just the right clone and coax it

into performing in large bioreactors, but

plant-manufactured proteins are well tol-

erated by humans and non-immunogenic

in sustained administration.”

“Bacterial cells, such as E. coli [Escherichia

coli] cell lines, however, are unable to pro-

duce complex, mammalian-like glycosyl-

ation due to the absence of the necessary

enzymatic components and the intracel-

lular compartmentalization required,” Ryan

adds. Although, as he points out, bacteria

offer a cheaper alternative to mammalian

cell lines. “Insect systems can also be useful,”

Ryan continues, “but haven’t really broken

through (except for a flu vaccine) yet, and

there is a potential risk in that baculoviruses

can be taken up by mammalian cells, which

is little appreciated.”

A major disadvantage for yeast expres-

sion systems is the relatively low yield

achieved when using these lines, explains

Ronen Tchelet, Dyadic’s chief scientific

officer. “Yeast expression systems have a

relatively low yield in comparison to the

current CHO cell lines and the produc-

tion of high mannose residues within the

expressed PTMs (50–200 vs three mol-

ecules in human cells, as part of either N-

or O-linked glycan structures),” he adds.

“This change in the glycoform’s structure

may confer a short half-life and render pro-

teins less efficacious and immunogenic in

humans. C1 is head and shoulders above

this cell type for the reasons noted above.”

Higher titers are always desirable

within the industry, but when titers are

driven primarily by transgene copy num-

bers, there is a possibility that genetic

loci can become unstable, which can

lead to titers lowering during the manu-

facturing process, reveals Cunningham.

“Furthermore, high titer processes that

are driven predominantly by maximizing

biomass can make downstream process-

ing complex, impacting product quality.”

LOOKING AT THE FORESEEABLE FUTURE As has been discussed earlier, there is an

increasing emphasis being placed upon

speed and cost within biopharma, states

Ryan. “At iBio, our technology obviates

the need to spend months isolating a

cell clone, allowing process development

to begin within a month of knowing

the target gene’s sequence.”

The cost and time pressures, which

Holton notes are already considerable

for the industry in terms of conventional

expression systems, will only propagate

with the advent of more personalized

medicines as well as growth in the biolog-

ics and biosimilars markets. “Mammalian

cell lines are slow to develop and expensive

to scale into production. In the coming

decade, a move towards rapid cheap and

scalable expression technologies, which are

capable of producing biologically active




Upstream Processing

human proteins, such as plant transient

expression, will begin to attain a growing

market share,” he says. “The pharmaceuti-

cal sector is extremely conservative and

risk averse, so these changes in production

will likely not occur quickly.”

Concurring with the speed and cost

issues surrounding mammalian cell lines,

particularly CHO, Emalfarb stresses that

time should not be wasted by the indus-

try thinking that CHO lines are a viable

future option of choice for the industry as it

moves into this next phase of more efficient,

speedy, and cost saving bio-manufacturing.

“CHO cells grow too slowly, they require

an enormous amount of money and energy

to feed with nutrients and expensive media

to force the CHO cells to grow and pro-

duce relatively low levels of protein per day

resulting in high capital and operational

expenditure. All to get a mediocre gram per

liter output. The COGS here don’t make

sense compared to our C1 fungal platform

for example,” he says.

For Cunningham, CHO-based mam-

malian cell expression systems will main-

tain dominance of the bioprocessing

space, at least for the foreseeable future.

“However, efforts will also continue to

develop non-CHO expression systems,

particularly to support vaccine and gene

therapy applications,” he adds. “I antici-

pate that, given the pressures to reduce

biopharma costs, there will be continued

research focused on increasing speed and

reducing cost to clinic in order to acceler-

ate the bench to bedside timeline.”

The ability to continually manufacture

a product rather than through batch pro-

cessing, perfusion, is an area of interest,

according to Kohli. “Perfusion, however,

presents a number of challenges, particu-

larly around how developers assess qual-

ity and titers on an ongoing basis and

whether key quality indicators remain

intact throughout the entire process,” he

notes. “Should products fall outside of

quality parameters, for example, it’s vital to

have measures in place that will segregate

material that does not meet these criteria.”

“The processes of the future and those

of today must rely on biomanufacturing

techniques that are efficient, robust, and

of high quality,” confirms Saunders. “It is,

therefore, imperative that the expression

systems and processes of the future con-

tinue to effectively isolate and identify the

very best cell lines and strains.”

Additionally, Saunders emphasizes the

point that despite considerable increases

in titers being witnessed over recent years,

there is still more work to be done in this

area. “Difficult-to-express molecules are

still expressed at considerably lower titers

and improvements must be made in order

to achieve suitable expression levels to

make them commercially viable,” she says.

To be able to express novel entities,

Saunders believes that there is a need to

move away from traditional cell line or

strain development. “Therefore,” she con-

tinues, “there will more than likely be a

rational re-design of existing expression

systems or efforts put into identifying

novel systems.”

STREAMLINING STARTS UPSTREAM“Streamlining the whole biologics process

certainly starts with upstream processes,”

states Natasha Lucki, product manager

at Thermo Fisher Scientific. “Researchers

want to improve and make the overall

process more efficient to shorten timelines.

The idea of getting to the market first will

always be at the forefront of developers’

minds, especially as new categories of bio-

logics come into the pipeline.”

According to Lucki as new tech-

nologies continue to enter the bio-

pharma space, a focus for scientists and

developers will be to take a holistic

approach toward the product pipeline.

“Developing processes that will facili-

tate not one, but the entire biologics

production chain from upstream to

downstream,” she adds. “For biopharma

companies, increasing efficiency and

enabling greater output while keeping

quality in mind are very important.”

Matthew Jones, Dyadic’s chief com-

mercial officer, stresses that despite it

being known that CHO cell lines are

less time and cost-effective than alterna-

tive systems, there is a lethargic resistance

to change by the industry. Risk adverse

industries need pace setters that positively

disrupt. “We need CEOs of biopharma to

engage and look at the viable options for

quicker and cheaper development of new

biologic entities,” he continues. “CHO

cells grow slower, require expensive media

to produce mediocre protein yields result-

ing in higher fixed and operating costs as

well as expensive drug discovery processes.”

Emalfarb goes further stating, “Modern

advances in the use of synthetic biol-

ogy technologies has come to cell lines.

Alternatives, such as Dyadic’s C1 fungal

cell line, can offer more rapid growth

at a lower cost, while producing higher

amounts of protein per fermenter day.

Not to move away from CHO to alterna-

tive lines is ignoring the incredible sci-

entific breakthroughs and advances that

are occurring faster in biopharma than

Moore’s Law did for tech.”

For Ryan, biotherapeutics are at an

interesting point with many novel and

cutting-edge medicines under develop-

ment in the laboratory. “Indeed, finding

the sweet spot among several competing

priorities—speed, cost of goods, biological

activity, non-immunogenicity (except vac-

cines), and ease of purification—is impor-

tant moving forward,” he says. Therefore,

other expression systems, such as iBio’s

transient plant expression system, may

play an important role in transitioning

these new products from the lab bench to

the bedside of the patient, he asserts.

“The sector is under intense and grow-

ing pressure to increase R&D efficiency,

to bring new drugs to market faster, and

to manage costs more effectively,” sum-

marizes Holton. “While there is no sil-

ver bullet to address all these challenges,

adopting highly efficient next-generation

expression systems, such as plant-based

systems can accelerate progress towards

these goals.”

REFERENCE1. Allied Market Research, “Global

Biopharmaceuticals Market: Opportunities and Forecasts, 2018–2025,” alliedmarketreseach.com, Report (July 2018). ◆



Sponsored by

Presented by

EVENT OVERVIEW:

Host cell proteins (HCPs) are more than a check-off box on

an investigational new drug or biologics license application.

Knowledge of what HCPs are present can inform purification

strategies to reduce the HCP level in drug substances. In this

webcast, experts will discuss the integration of orthogonal

methods for comprehensive HCP analysis, present data showing

HCP identification by mass spectrometry (MS) before and after

Antibody Affinity Extraction (AAE), and highlight how this infor-

mation provides actionable insights into downstream process

development and purification improvements.

Topics to be addressed include the following:

■ Importance of detailed Information of HCP profile

■ Antibody Affinity Extraction

■ Role of mass spectrometry in HCP analysis

■ Antibody Affinity Extraction and mass spectrometry case

studies

Key Learning Objectives

■ Learn why Antibody Affinity Extraction (AAE) is a superior

alternative to 2D Western blotting for HCP antibody coverage

analysis

■ Understand how enrichment of HCPs by AAE and

identification by mass spectrometry is a powerful alternative

orthogonal method to enzyme-linked immunosorbent assay

■ Learn how biopharmaceutical companies that integrate MS

with ELISA data can provide comprehensive quality control

data for regulatory agencies

Who Should Attend

■ Bioprocessing scientists, process engineers,

managers and directors

For questions contact Martha Devia at [email protected]

Presenter

Jared Isaac, PhD, MBA

Senior Scientist, Research

and Development

Cygnus Technologies

Moderator

Rita Peters

Editorial Director

BioPharm International

Register for this free webcast at www.biopharminternational.com/bp_p/extration

LIVE WEBCAST: Tuesday, June 18, 2019 at 11am EDT | 8am PDT | 4pm BST | 5pm CEST

Empowering HCP Identification with

Antibody Affinity Extraction™ (AAE)

and Mass Spectrometry


http://www.biopharminternational.com/bp_p/extration





Downstream Processing

Addressing the Complex Nature of Downstream Processing with QbD

Quality by design brings both challenges and benefits to the development of downstream processes.

SUSAN HAIGNEY

Regulators have been encouraging bio/pharmaceutical

companies to incorporate the concept of quality by

design (QbD) into development and manufacturing

processes for more than a decade. The International Council

for Harmonization (ICH) defines QbD as a systematic

approach that incorporates prior knowledge, results of stud-

ies using design of experiments (DoE), use of quality risk

management, and use of knowledge management throughout

a product’s lifecycle (1). QbD incorporates the identification

of critical quality attributes (CQAs) through a quality target

product profile (QTPP). Critical material attributes (CMAs)

and critical process parameters (CPPs) are identified through

product design and understanding. Specifications for the drug

substance, excipients, and drug product and controls for each

manufacturing step are determined through a control strategy.

The final elements of QbD are process capability and con-

tinual improvement (2). These steps combine to build quality

into pharmaceutical processes and products over the lifecycle

of a pharmaceutical product.

The industry has been slowly adopting the QbD

approach, but with the boom in the biopharma indus-

try, how have these QbD principles fit into the complex

nature of biologics? According to Gunnar Malmquist,

principle scientist, GE Healthcare, QbD has become

an integral part of the development process for the bio-

pharma industry. “We notice that the interest to file

according to the QbD framework has cooled off during

the past several years, but it is common during biophar-

maceutical development to utilize and align with the prin-

ciples of QbD as part of development activities. Nowadays,

it is a structured methodology for how to approach prod-

uct development that is not driven by regulatory need, but

rather internal needs related to the establishment of pro-

cess understanding,” says Malmquist.

CHALLENGES OF QBD IN DOWNSTREAM PROCESSINGWith the complex nature of biologics comes more com-

plex quality concerns. Joey Studts, director late-stage

downstream development in the bioprocessing develop-

ment biologicals department at Boehringer Ingelheim

(BI), notes that large-molecule products have more input nata

li_m

is/S

tock

.Ad

ob

e.c

om





parameters that could possibly affect

qual i t y. “From my understand-

ing, the number of input parameters

that can have a significant impact

on product quality is higher in the

large-molecule world due to the

multiple biologically based upstream

unit operations and the complexity

of assigned direct correlations,” says

Studts.

Therefore, using QbD to design

downstream processes has its chal-

lenges. One challenge is the unpre-

dic tab le re la t ionships between

molecular properties and down-

stream processes, but there is also the

opportunity to concentrate efforts

on the areas that are most impor-

tant, says Malmquist. “Especially for

novel molecular formats, one of the

remaining challenges is the com-

plex relationships between molecular

properties and downstream processes,”

explains Malmquist. “In addition,

the inherent high risk for drug fail-

ure at early stages of development

combined with short development

timelines suggests the need for a plat-

form approach to manage the early

phases of drug development and con-

duct more detailed characterization

towards late-stage process develop-

ment,” he says.

To a d d r e s s t h i s c h a l l e n g e ,

Malmquist recommends rely ing

on process steps that are less risk

exposed to avoid unpredictabil-

ity. “For instance, protein A or affin-

ity resins in general, as well as flow

through steps, display these proper-

ties since these steps in most cases

build on a fundamental understand-

ing of the physiochemical phenomena

involved in their performance,” he

says.

The removal of product-related

impurities is another challenge,

according to Malmquist. “In these

instances, characterization of the

interplay and impact of process

parameters and raw material attri-

butes is required to fully align with

the QbD methodology, which trans-

lates into extended process develop-

ment and characterization efforts.

The effort can be reduced by a risk-

based approach where the studies are

focused on the most important (or

less well-known) factors.” To address

this, the use of mechanistic modeling,

and other emerging techniques, can

reduce the experimental burden and

concentrate efforts to attributes dis-

playing the highest risks, Malmquist

says.

“Typically, process parameters and

their variability are well character-

ized, whereas the interplay between

them and, for instance, resin vari-

ability may represent a blind spot,”

says Malmquist. The impact of vari-

ability regarding raw materials can be

felt first in commercial manufactur-

ing because of a lack of relevant test

material during process characteriza-

tion. “The only viable approach to

become more proactive is to engage

in a true partnership with the raw

material suppliers to share knowl-

edge, get access to relevant samples

to develop a successful control strat-

egy,” he adds.

When it comes to early devel-

opment, Doug MacDonald, senior

scientist at Seattle Genetics, a biotech

company that develops and commer-

cializes cancer therapies, states that

“speed to clinic” can inhibit the appli-

cation of QbD. “Our typical IND

[investigational new drug] timelines

assume that the protein will fit the

platform and therefore won’t require a

lot of additional development efforts.

We have definitely seen therapeutic

proteins becoming more complex and

have had challenges at times with the

downstream process. In one case, we

had an engineered antibody, which

possessed properties that were not

entirely amenable to our platform

purification process.”

The company developed a new

platform process for these types of

proteins by doing a large amount of

the work early on. “The knowledge

we gained during that process will

definitely help in the later potential

scale-up and commercialization of

the product; however, having more of

a characterized operating space is not

typical in the [Phase I] development

process. It is important for QbD to

link early and late-stage processes,

and to address this we have changed

our platform to be representative

of the potential commercial pro-

cess. We have also developed many

high-throughput tools applicable to

process and product development

within upstream, downstream formu-

lations, and analytical development,”

MacDonald says.

THE BENEFITS OF QBD IN DOWNSTREAM PROCESSINGWhen developing processes for down-

stream applications, companies are

using QbD to develop and track

goals and evaluate risk of develop-

ment processes and steps. Seattle

Genetics takes a holistic approach

to downstream process development,

according to MacDonald. “In early

development, we leverage platform

data to expedite the time to produce

tox material test article and clinical

material. However, for later stage and

commercial, we employ detailed risk

assessments based on FMEA [failure

modes and effects analysis] concepts

to guide the needed studies and scope

Use of mechanistic

modeling can reduce

the experimental

burden and

concentrate efforts to

attributes displaying

the highest risks.





of work. These risk assessments are

influenced by platform data, previ-

ous process characterization knowl-

edge, available GMP data, and subject

matter expertise. DoE activities are

applied where appropriate models are

generated to characterize the study

space and possible impacts the process

has on the product,” says MacDonald.

QbD should also be used to docu-

ment and track the progress of pro-

cess development goals, according

to Studts. “We use the therapeutic

and clinical goals of the program as

defined in the QTPP to execute a risk

assessment of the quality attributes to

clearly define the CQAs for the pro-

cess and use these as a basis through-

out development.” Studts says CQAs,

process performance, and other goals

should be written in a development

protocol document. Experiments

should then be designed and executed

so that relationships can be defined

between input and output parameters.

QbD can be applied down to spe-

cific process levels as well, including

the development of process mate-

rials. GE Healthcare uses QbD in

the company’s development of resins.

“General Electric has for a long time

used a Design for Six Sigma, which

is built on the same principles as

QbD. For resin development at GE,

this means that external user needs

are converted to functional proper-

ties that can be measured internally

during resin development. These are

matched to structural properties of

the resin that plays the same role

as quality attributes in QbD. These

potentially critical resin characteris-

tics are always studied together with

chromatographic process parameters

at relevant process conditions during

our development to ensure productiv-

ity and robustness,” says Malmquist.

Some downst ream processes

require more rigorous study than

others, according to MacDonald.

“Polishing steps such as ion exchange,

hydroxyapatite, and hydrophobic

interaction chromatography can be

more heavily influenced by pH, con-

ductivity, loading capacity, residence

time, and temperature, and therefore

would benefit more from a QbD

approach. These steps are typically

designed with more specific product

attributes in mind and need more

fine-tuning to achieve a goal of prod-

uct or process related impurity or

virus reduction,” says MacDonald.

When platform data already exist,

others may require less study, such

as affinity chromatography steps,

low-pH viral inactivation, and nano-

filtration, says MacDonald. “There

can always be a need to study these

steps further, and the expectation is

to do so at later-stage process char-

acterization; however, the number of

parameters requiring defined operat-

ing spaces may be reduced because

of the nature/modality of the step.

Nanofiltration is difficult and expen-

sive to study since the designated

CPP impact on a product CQA is

the viral content, which can only be

tested at approved CROs [contract

research organizations].”

According to Malmquist, opera-

tions that have the greatest impact

on the quality target product pro-

file get the most benefit out of QbD.

Understanding how the interplay

between process parameters, raw mate-

rial attributes, and the control strat-

egy may affect CQAs could potentially

reduce risk and improve development

speed, says Malmquist.

“An example is the topic of product

aggregates that can trigger immuno-

genic responses. It is therefore com-

mon to reduce aggregate content to

below a threshold value using cation

exchange, multimodal chromatogra-

phy, or hydrophobic interaction chro-

matography. For this kind of step, it is

important to understand the process

parameters such as load ratio, buffer

ranges, as well as resin ligand density

when developing the control strategy,”

says Malmquist.

While Studts believes all process

steps benefit from QbD, platform-

based unit operations with previously

established input and output param-

eters are not “actively developed with

QbD principles.”

“Process steps or unit operations

where the quality attributes are

impacted by input parameters within

the step require product-specific data

and therefore benefit from an active

QbD approach. Regardless whether

platform or product-specific param-

eters are used, each unit operation

benefits from having a clearly defined

target or target range for the unit

operation. With output target ranges

clearly defined, the variability of the

input parameters is tested to define

a proven acceptable range (PAR).

This PAR is then compared to the

uncontrollable variability of the input

parameter or normal operating range

(NOR). With these two input ranges

set and considering the equipment

capability around the input param-

eter, the risk of this parameter is

assessed, and criticality assigned. The

risk assessment and criticality assign-

ment are then the basis for the control

strategy,” says Studts.

QBD IN VIRAL CLEARANCEViral clearance is connected to patient

safety, according to Malmquist. During

Contin. on page 32

Operations that

have the greatest

impact on the

quality target

product profile get

the most benefit out

of QbD.



EVENT OVERVIEW:

Owing to the impact on drug efficacy and safety, glycosylation has

long been recognized as a critical quality attribute that requires

in-depth characterization and close monitoring throughout the

product lifecycle of biotherapeutics. Glycosylation is generally

assessed at a released glycan level using fluorescence (FLR) detec-

tion to overcome the challenges in structural complexity and broad

concentration range. While sensitive optical detection alone often

lacks the specificity needed for unequivocal glycan structural deter-

mination/assignment, orthogonal technologies, such as high-reso-

lution mass spectrometry (HRMS), can provide additional structural

information. These technologies, however, face great difficulty to

deploy in process development and manufacturing environments

due to instrumentation and analytical methodology complexity.

In this webcast, participants will learn about:

■ An easy-to-use workflow developed on the compact and

integrated LC-MS System that can be efficiently deployed across

organizations

■ An end-to-end streamlined workflow for released N-glycan

analysis from sample preparation to liquid chromatography

(LC)-FLR-MS analysis thru reporting

■ Improved productivity and reproducibility with automated

sample preparation

■ Case studies demonstrating how the simplified analytical

workflow transforms high quality LC/FLR/MS data into

meaningful results for released N-glycan analysis

Register for this free webcast at www.biopharminternational.com/bp_p/bioaccord

SERIE S | PAR T II

Improving Confidence and Productivity in Released Glycan Analysis for Biotherapeutic Development

LIVE WEBCAST: Wednesday, July 17, 2019 at 11am EDT | 8am PDT | 4pm BST | 5pm CEST

PART I: Transforming High Performance LC-MS Analysis in Biopharma: From Molecular Characterization to Attribute Monitoring

ON-DEMAND WEBCAST Aired May 16, 2019

PART III: Developing a Robust CQA Monitoring Method via Multi-Attribute Monitoring Principles for Therapeutic Monoclonal Antibody Development, Manufacturing, and Lifecycle Management

LIVE WEBCAST: Tuesday, September 10, 2019

at 11am EDT | 8am PDT | 4pm BST | 5pm CEST

Register for the whole series:

Presenter

Ximo Zhang Senior Scientist, Biopharmaceutical Scientific Operations Waters Corporation

Moderator

Laura Bush Editorial Director LCGC

Sponsored by Presented by

For questions contact Kristen Moore at

[email protected]


http://www.biopharminternational.com/bp_p/bioaccord



http://lcgcindia.com/

https://www.waters.com/waters/home.htm?locale=en_IN


Peer-Reviewed

ABSTRACTThe authors present a risk analysis of the impact of various

business and operating risks on three facility layout strategies.

MARK F. WITCHER AND HARRY SILVER

Eff icient ly and rel iably manu-facturing biopharmaceutica ls requires controlling business and operating risks using enterprise

control strategies (ECSs). ECSs are built using the three manufacturing enterprise elements—process, facility, and infrastruc-ture (1). The facility element includes the facility’s layout strategy. The layout can be used to decrease the likelihood of realizing both business risks associated with prod-uct development and manufacturing, and risks associated with operating sequences of process unit operations (UO) grouped into logical operating units (LOUs) nec-essary for manufacturing products. After defining the goals of all control strategies (CSs) and brief ly describing an enterprise’s control elements, this article compares the impact of several common facility layout strategies, including the multi-purpose facility (MPF) (2, 3), on managing impor-tant business and operating risks.

MANUFACTURING FACILITY DESIGNSFacility design layout strategies used within the biopharmaceutical industry generally fall into three categories:

• Purpose built facility (PBF)—Layout is designed around the process equipment required to implement a well-defined UO/LOU sequence for a process or set of processes. Large-scale manufactur-ing facilities designed around f ixed stainless-steel systems are PBFs. The

PBF may also use some or all single-use technologies. However, when a PBF is designed, the process implementation is simultaneously integrated into the facility layout to achieve the desired efficiency, segregation, and operating f lows. PBFs may have more than one production train. Multiproduct manu-facturing is usually executed on a cam-paign basis within a single process train. Flexibility is limited to process formats included in the initial design. Adapting a PBF to new processes can be expen-sive or not feasible because of ongoing manufacturing requirements.

• Shared f lexible space facility (SFSF)—Layout design is based on using large open spaces for either f ixed or move-able single-use technology or stainless-steel equipment required for making one or more products. The layout com-mingles a large number of UOs for one or more processes and products in a f lexible open ballroom configuration. Segregation may be limited to large LOUs such as upstream and down-stream, or specialize activities such as bulk filling. Operations within large spaces are conducted by common per-sonnel to achieve labor eff iciencies. Multiproduct operation may or may not occur within shared spaces. The simple layout of the SFSF reduces capi-tal investment requirements. Amgen’s Singapore facility is an excellent exam-ple of the SFSF layout concepts (4).

Mark F. Witcher, PhD

is a consultant,

[email protected].

Harry Silver is senior process/facility

designer at Harry Silver

Designs.

PEER-REVIEWED

Article submitted:Feb. 13, 2019

Article accepted:March 19, 2019

STA

RK

OV

PH

OT

O -

ST

OC

K.A

DO

BE

.CO

M

Comparing Facility Layout Options for Managing Business and Operating Risks





Peer-Reviewed

• Multi-purpose facility (MPF)—Facility layout, as shown in Figure

1, is based on a matrix of small non-dedicated, multifunctional operating areas accessed by pri-mary and out corridors allowing both bi and unidirectional f low of materials, equipment, and person-nel. Multiproduct manufacturing is accomplished by placing prod-uct dedicated LOUs using movable single-use technology or stainless-steel equipment within a variety of possible room configurations capa-ble of operating the process (2, 3). Advantages of MPF are similar to the SFSF except the MPF is more complex due to the increase in the number of rooms, corridors, and other facility systems.

Each facility layout strategy has strengths and weakness. The PBF has been the classic layout strategy used to design biopharmaceutical facili-ties, particularly those for operating large stainless-steel systems for a well-defined process. The SFSF was devel-oped using single-use technology to provide additional operating flexibility and reduce facility complexity to lower capital investment (4). The MPF was proposed to speed up the launching of new products by providing suff i-cient scale and process implementation flexibility to operate a wide variety of process formats and simultaneously support pre-clinical, clinical, and com-mercial manufacturing with minimal tech transfer time and effort (2, 3).

CONTROL STRATEGY GOALSAll manufacturing control strategies, including enterprise-wide control sys-tems (ECSs) have three goals: • State of control—Provide a quali-

f ied robust control strategy that reliably controls all the process’s operating steps to achieve pre-defined product material attributes and process behavior quality met-rics that assures each step can be released for executing the following operating step, including release of final product.

• Proof of control—Provide docu-mented release based on product and process quality metrics at control points for each operating step to allow release for execut-ing the next step. The informa-tion should be sufficient to prove to an unbiased external reviewer that the step was completed as planned and def ined. Proof of control can be, by far, the hardest goal because it sometimes requires

“proving a negative” associated with establishing that a failure of an external operation within the same manufacturing enterprise did not impact UO steps for other processes or products.

• Return to control—Should an operating step not pass its release

criteria, assure suff icient process information is collected to deter-mine the failure’s impact on prod-uct quality and rapidly return the step to a state of control using an investigation, including a root cause analysis.

Achieving all three goals is a dif-ficult task, particularly when dealing with multiproduct manufacturing of a wide range of upstream and downstream UOs combined into a variety of LOUs to achieve impor-tant operational and process segre-gation requirements (e.g., pre- vs. post-viral, etc.). Control strategies designed to achieve all three goals must be constructed using an eff i-cient combination of the following ECS elements. F

IGU

RE

S A

RE

CO

UR

TE

SY

OF

AU

TH

OR

S.

Figure 1. Matrix layout. Facility layout shown is a matrix of individual non-dedicated multi-purpose rooms in three arms (A–C) each having six rooms (1–6) that can be independently configured to house a variety of process and support function LOUs necessary to achieve the require manufacturing capabilities. All equipment, primarily single use, is movable for placement or relocation within the matrix as required to operate a wide variety of process implementations. The facility can be expanded by increasing the number of arms and the number of rooms in each arm in the initial design or adding arms later above the out corridor at the top of the figure (2, 3).




Peer-Reviewed

ELEMENTS OF ENTERPRISE CONTROL STRATEGIES

A pharmaceutica l manufacturing enterprise can best be described by three elements that are combined to complement each other to achieve the above control strategy’s goals. Each element provides important tools for building effective control strategies. The most efficient and effective ECSs use an appropriate balance of the fol-lowing elements (1): • Process—UOs, grouping of UOs

into LOUs, process equipment, components, instruments, auto-mated process control systems, input and in-process materials, and products. Process systems can include stainless-steel and single-use systems.

• Facility—Buildings, environmental systems, layouts, operational f lows, logistical support, utility systems, and other building control systems such as the building management system.

• Infrastructure—Practices, proce-dures, people (training, discipline, and qualif ication), maintenance systems, and automated procedural control systems (MES, EBR, etc.) that control the facility and process elements.

The enterprise can be summarized as “the process operating inside the facility under the control of the infra-structure” (1).

With the control strategy’s goals and the enterprise elements for build-ing ECSs def ined, the foundation of the risk management method for

understanding the layout’s impact on controlling various risks can be described.

RISK ANALYSIS APPROACHThe risk analysis approach is a system risk structure (SRS) methodology (5). SRS is based on a threat—process—risk consequence model shown in Figure 2 for business risks and Figure 3 for operating risks. SRS describes the likelihood that one or more threats, such as an input failure or change in the risk process, will result in a neg-ative risk consequence (5). The risk process can be designed or redesigned to control the risk by decreasing the likelihood that the threat will success-fully pass through the risk process to result in the realized risk.

A SRS’s risk process can be any-thing from an entire manufacturing facility, in this case the facility’s lay-out, to a simple piece of equipment or procedure depending on the scope of the risk analysis. Based on the pro-cesses to be evaluated, the risk pro-cesses can be combined into sequences similar to a process f low diagram (PFD) to form a SRS for analyzing complex risk problems (5, 6). Because all risks are assumed to be output con-sequences from a risk process caused by an input threat or trigger, the only difference between a threat and risk is the process it comes from in the PFD or SRS.

In this article, the risk process is limited to one of the facility layout strategies (PBF, SFSF, or MPF). If the facility layout does not control

the risk by adequately mitigating the likelihood of the threat’s impact, then the risk must be either accepted, or other ECS elements, such as scheduling, procedures, and facil-ity modifications, must be added or enhanced as necessary to provide suff icient control of the threat. In the past, some of the business risks described in the following have fre-quently been accepted as a “fact of life” (e.g., product delays, shortages, additional capital costs, etc.) with great negative impact on patients and the business’s bottom lines.

The following risk analysis sub-jectively rates the severity and like-lihood of various threats and risk consequences relatively to each other. The subjective ratings are based on the author’s 33 years of engineering, operations, and risk analysis experi-ence in the biopharmaceutical indus-try (5, 6). When evaluating different layout options, each company should make the same ratings based on their specif ic situations, experience, and expertise.

SIGNIFICANT BUSINESS THREATS AND RISKSThe following discussion is limited to a few important representative threats and risks that could possibly occur to the manufacturing enterprise. Figure 2 sum-marizes a few of the business threats (BT) and business risks (BR).

The threats are risk consequences that result from threat processes (e.g., from a prior or secondary threat) not described in this analysis. The

Figure 2. Business risks (BR) and threats (BT) that may adversely impact the manufacturing enterprise. The discussion focuses on the relative likelihood of three facility layout strategies (PBF, SFSF, MPF) controlling the threat’s ability to produce the risk consequences. PBF is purpose built facility. SFSF is shared flexible space facility. MPF is multi-purpose facility.




Peer-Reviewed

likelihood of the secondary threats occurring is assumed to be indepen-dent of the layout selected and thus outside of the scope of this discussion.

1. Changes in product demand (BT1)—Market forecasts have not accurately anticipated product demand. 2. Product failures during develop-ment (BT2)—Product fails during clinical testing and no longer needs to be manufactured. 3. Uncertainty in process design and format (BT3)—During pro-cess development, the UO/LOU sequence or format for a new product is signif icantly different than previous processes (e.g., from batch, used to design the facility’s layout, to an intensif ied or con-tinuous process). 4. Insufficient or excessive support resources (BT4)—Capacity limita-tions resulting from and inability to supply the process with sufficient media or buffers. 5. Inefficient facility layout (BT5)—The layout increases operating labor or capital investment. Although the business threats vary

widely between companies, their impact severity on patients and eco-nomic sustainability can be ranked qualitatively relatively to each other (> greater than, >> much greater than) in the following order: (BT1>BT2 >> BT3>BT4 > BT5).

Each of the layouts could be impacted by any of the threats indi-vidually or collectively to result in the risks described as follows. Each risk will be brief ly discussed in terms of the layout’s overall ability to decrease the likelihood of the threat’s impact on producing the risk. A detail analy-sis is left to each company to under-stand the impact of the threats and risks on selecting a layout strategy.

The fol lowing BRs shown in Figure 2 are subjectively evaluated with-out considering the interactions with the operating risks. Realization of operating risks can also have a significant impact on any or all of the following BRs:

1. Insuff ic ient manufactur ing capacity (BR1)—Demand for clini-cal or commercial material cannot be supplied because manufacturing capacity is unavailable or existing manufacturing capacity cannot run the required process.

Relative likelihood rating: BT1 >>

BT3 > BT4.

Unless initially constructed (an exposure to BR3, BR4, and BR5), expansion of the PBF’s capacity requires the time and capital for building a new facility or exten-sively modifying the existing layout. The SFSF can prioritize product campaigns, but rearranging pro-cesses in different configurations and formats (BT3) may be diff i-cult to achieve without interfering with on-going manufacturing and increasing operating risks. Because of it s h igh f lex ibi l-ity, the MPF can quickly priori-tize products to increase capacity or be quickly expanded by adding additional suite rows at the top of Figure 1 with minimal impact to ongoing production.

Relative overall threat mitigation rat-

ing: MPF > SFSF >> PBF

2. Delayed product launch (BR2)—An inability to launch a product due to the unavailability of manu-facturing capacity.

Relative likelihood rating: BT1 >

BT3 > BT4.

Having capacity creation on the critical path can have a signif i-cant impact on the approval pro-cess, patient health, and business revenue. The impact of prebuild-ing capacity (BR3, BR4, BR5) is signif icant and depends on the f lexibility of the facility to accom-modate different processes asso-ciated with other products in the pipeline.

PBFs are typically not designed for scale f lexibility or eff iciently adaptable for both early clinic and commercia l-sca le process cam-paigns. Including options for scale and process f lexibility significantly increases capital investment. SFSFs may be designed with sca le f lexibi l it y, but extensive infrastructure control strategies are required to manage commingled multiproduct pre-clinical, early clin-ical, and commercial production. The segregated matrix of the MPF provides a great deal of process scale and format f lexibility.

Relative overall risk mitigation rat-


3. Excess or unused manufactur-ing capac it y (BR 3)—Unused manufacturing capacity because of BT1, BT2, BT3, and BT4. BR3 is concomitant with BR4 and BR5.


BT1 >> BT3, BT4.

The PBF is the most likely to be oversized because it may have to accommodate future capac it y growth associated with possible market expansion. Other products produced in the PBF would have to have similar processes. The SFSF has some f lexibility to manipulate its equipment arrange-ment to adapt to other product’s processes, but product change-overs are more diff icult during produc-tion of other products. The MPF can quickly adapt to other products for clinical or com-mercial manufacturing regardless of scale and process format.



4. Higher capital investment (BR4)—Excess capital investment might result from building unneeded or unusable manufacturing capacity,




Peer-Reviewed

including an inability to manufacture pre-clinical or early clinical products in the pipeline; concomitant with BR3. The risk of spending too much capital is largely dependent on the flexibility of the facility to adapt to the threats.


BT1 > BT3.

If the PBF is designed for process and capacity f lexibility to handle capacity uncertainty, capital costs increase significantly. The SFSF’s f lexibility may be lim-ited by ongoing manufacturing, and unanticipated process formats may be difficult to incorporate. MPFs have signif icant f lexibil-ity and thus are more likely to be usable for manufacturing new prod-ucts over their entire lifecycle.



5. Higher cost of goods (COG) (BR5)—Facility is inefficient and results in a higher cost of goods for making clinical and commercial products. This risk can be caused by threats BT1 and BT2; concomitant with BR3 and BR4.


BT1 >> BT3, BT4 > BT5.

For a well-def ined process with known capacity requirements, PBFs

often can provide the lowest COG. However, COG may increase sig-nificantly as the uncertainty of the process def inition and capacity requirements increase. The SFSF can control costs by sharing operating labor within common areas allowing staff to work on multiple LOUs at the same time. However, COG may increase and operating f lexibility may decrease due to control strate-gies additions required for operat-ing commingled processes. The COG advantage of the MPF relies on its f lexibility to achieve a higher utilization rate under high uncertainty from being able to manufacturing many different clin-ical and commercial products using a wide range of different processes.



OPERATING THREATS AND RISKSOperating risks are important second-ary threats to business threats that may ultimately produce business and patient supply risks. The analysis of how operating risks threaten busi-ness risks is outside the scope of this analysis. The layout can have a sig-nificant impact on mitigating operat-ing threats to prevent the likelihood of realizing operating risks shown in Figure 3.

The discussion here will be lim-ited to the operating risks caused by

the representative operating threats shown in Figure 3. To understand how the layout might control the threats to minimize or prevent the operat-ing risks, the risk process is again the facility layout. For layouts that provide minimal threat control, other ECS elements such as closed single-use systems, procedural, and time-based sequencing controls must be used to minimize the likelihood of the threats producing one or more operating risks.

The operating threats (OTs) are the result of secondary threats to operat-ing threat processes from equipment, components, procedures, and human operator errors used to operate the process and facility systems. In most enterprises, the largest source of sec-ondary threats are mistakes by operat-ing personnel (7, 8). In this analysis, the secondary threats are assumed to be independent of the layout. The fol-lowing are the representative operat-ing threats:

1. Facility contamination–other process (OT1)—Facility is con-taminated from an external opera-tion such as a second product in a multiproduct operation unrelated to the immediate process steps being evaluated. 2 . Fa i lure of UO changeover (OT2)—Failure to properly execute a lot or product changeout requir-ing clean-up and removal of single-use components or cleaning of a contaminated stainless-steel system. 3 . Fa i lu re to operat ing UO (OT3)—A fa i lure that occurs

Figure 3. Operational threats and risks that may adversely impact the performance of the manufacturing enterprise. The discussion focuses on the relative likelihood of three facility layout strategies (PBF, SFSF, MPF) controlling the threat’s ability to produce the risk consequences. UO is unit operations. PBF is purpose built facility. SFSF is shared flexible space facility. MPF is multipurpose facility.




Peer-Reviewed

during normal operation (e.g., a leaking bag or coupling or other equipment failure). 4. Failure to set-up UO (OT4)—A failure to properly setup a piece of equipment and prepare it for opera-tion (e.g., incorrect connection or damaged single-use bag, etc.). These threats, if real ized, can

result in the operating risks listed in Figure 3. Because of space limitation and incomplete knowledge of the pro-cesses, only the likelihood that the threat will result in a significant risk in the context of the facility’s layout is discussed. For this analysis, secondary threats are assumed to be independent of the layout strategy. The operating risks (ORs) are:

1. Product cross contamination (OR1)—The risk consequence is an undetected or undetectable cross contamination of one product or lot with another product or lot.

Relative likelihood rating: OT2 >>

OT3 > OT1.

The most important control objec-tive is proof of control. The less segregated the facility’s layout, the more reliance on closed single-use systems (a process ECS element) is required for preventing the risk. In general, single-use technologies are threatened by diff icult to control human factors during setup, opera-tion, and changeover. Controlling these secondary threats is diff i-cult, but achievable by using both process and infrastructure (timing, procedures, training, etc.) ECS ele-ments. The more UOs are com-mingled in a single space, the more complex the SRS making the ECSs to prevent both perceived and actual cross contamination more complex.

Relative threat impact likelihood rat-

ing: MPF > PBF >> SFSF

2. Facility contamination (OR2)—An equipment, procedural execution,

or component failure, such as a leak-ing single-use bag that results in a contamination of the surrounding facility.

Relative likelihood rating: OT2 >

OT3 >> OT4.

The extent of the process UO seg-regation plays a signif icant role in limiting the extent of the con-tamination’s impact on other pro-cesses. The complex SRS of the SFSF makes controlling the impact of a facility contamination difficult. The complexity of the SRS is a key factor in designing a PBF and an intrinsic advantage of the MPF.


ing: MPF >> PBF >> SFSF.

3.Personnel exposure (OR3)—Extent of exposure and ability to limit, isolate, and remove personnel from operating areas during a con-tamination event.


OT3.

The high process segregation and unidirectional f low capability of the MPF is a significant advantage for isolating and mitigating personnel exposure in the event of OT2 and OT3. PBF and SFSF layouts may include additional controls in their design, particularly personal pro-tection equipment.


ing: MPF >> PBF>SFSF.

4.Process contamination (OR4)—Process UO becomes contaminated resulting in the loss of a lot (e.g., bioreactor contamination).


OT1 >> OT3>OT4.

The l ike l ihood of a process contamination is impacted by

the number of threat interactions described by the SRS surrounding each UO. The more threat inputs to the UO, the more likely a con-tamination could occur (5).


ing: MPF > PBF >> SFSF

5. Operat ing schedule delays (OR5)—Failure of one process causing delay of or interference with the operation of another pro-cess LOU. OR5 is typically not significant unless it causes a train wreck that impacts multiple pro-cesses and products.


OT3 > OT1 >> OT4.

The more unit operations within a given space, the more procedural and scheduling controls will be required to prevent operational interference. The SFSF has the highest exposure to schedule “train wrecking” if operating threats occur at the wrong time in a large space executing numerous closely sched-uled operations.


ing: MPF > PBF >> SFSF.

CONCLUSION The bottom line on manufacturing facility layout risks is the uncertainty factors that impact reliability and uti-lization. The above risk analysis evalu-ates the impact of various business and operating risks on the three facility layout strategies. If the manufacturing enterprise knows exactly what will be made over the facility’s lifespan, the PBF with appropriate control strategies tailored to provide the defined process and capacity requirements is probably the most effective and efficient.

As the process and product uncer-tainties increase, the SFSF becomes more ef fect ive f rom its capita l and operating cost advantages for multi-process operation. The higher




Peer-Reviewed

operating risks of the SFSF must be controlled by comprehensive infra-structure elements (scheduling, pro-cedures, training, etc.) to mitigate a more complex SRS associated with the commingled processes.

When the process and product uncertainty become signif icant, the MPF has the advantage of the high process segregation that minimizes the SRS of the individual processes along with the MPF’s ability to effi-ciently adapt its resources to a variety of different process formats and scales. The MPF has the additional advan-tage of controlling operating risks that allow the facility to support the entire product manufacturing lifecycle.

The choice between the PBF, SFSF, and MPF’s layouts should be made by

each company to optimize utilization and reliability depending on the antic-ipated threat and risk uncertainties of the product portfolio and the pro-cesses it anticipates needing to operate.

REFERENCES 1. M. F. Witcher, “Impact of Facility

Layout on Developing and Validating Segregation Strategies in the Next Generation of Multi-product, Multi-phase Biopharmaceutical Manufacturing Facilities;” Supplement to Pharm. Engr. (Nov./Dec. 2013).

2. M. Witcher and H. Silver, Pharmaceutical Technology 42 (9) (2018), www.pharmtech.com/multi-purpose-biopharmaceutical-manufacturing-facilities-part-1-product-pipeline-manufacturing?pageID=1

3. M. Witcher and H. Silver, Pharmaceutical Technology 42 (11) (2018), www.pharmtech.com/

multi-purpose-biopharmaceutical-manufacturing-facilities-part-ii-large-scale-production

4. B. Bader, “Multiproduct Madness–Flexible Manufacturing Facility, Case Study Amgen MOF,” presentation at ISPE Biopharmaceutical Manufacturing Conference, San Francisco, CA, Dec. 4, 2017.

5. M.F. Witcher, BioProcess J, 16 (2017), https://doi.org/10.12665/J16OA.Witcher

6. Witcher, M. F., “Understanding and Analyzing the Uncertainty of Pharmaceutical Development and Manufacturing Execution Risks using a Prospective Causal Risk Model”, Submitted to BioProcess J. 2019.

7. T. Muschara, Risk Based Thinking–Managing the Uncertainty of Human Error in Operations, Routledge (Taylor & Francis Group, 2018).

8. G. Peters and B. Peters, Human Error–Causes and Control (CRC Taylor & Francis, 2006). X

downstream processing, virus inac-tivation, virus f iltration, and chro-matography steps are performed. Malmquist believes designing viral safety into processes from the begin-ning is of “high value … delaying the testing to comprise validation and at the same time reducing the risk for surprises at late-stage process devel-opment. This can be done through linking understanding of how viruses can be cleared at different process conditions, this information can be utilized across development projects and reduce team effort and increase speed,” he says.

Platform knowledge may be used to design most viral clearance steps, and if the molecule is performing in accept-able ranges, a control strategy can be set from historical data, according to Studts. “BI sees the implementation of platform knowledge to define NORs and PARs as well as a control strategy as QbD. In such cases, a few optimally designed experiments are executed to understand the sensitivity of the spe-cific molecule to the unit operation and the platform parameters being imple-mented, and a full DoE- based series

of experiments are not necessary,” says Studts.

When it comes to monoclonal anti-bodies, MacDonald says that viral clearance processes are “widely known and understood”, with most plat-forms being developed for effective and orthogonal approaches for inac-tivating and removing viruses. “The A-Mab case study is a good example of supporting the platform approach to viral clearance (3). We are always mindful that as new data emerges, process development (PD) scientists may need to evolve their strategies. For a long time, people thought that high-pressure operation of nanofilters was considered ‘worst-case’. In recent years, data have come out justifying the opposite. In response, we have started testing our lowest operating pressure as part of the viral clearance validation package. Pressure excur-sions, including what may happen during product recovery buffer f lushes, have sometimes been shown to lead to viral break-through during valida-tion studies. We have adopted a risk mitigation strategy in response: we no longer buffer f lush our nanofilters to

recover the remaining product, essen-tially taking a yield loss on the step to ensure a quality product. We feel that this approach specif ically addresses QbD,” MacDonald states.

CONCLUSIONDespite the complex nature of biolog-ics, Studts believes that QbD can be applied effectively in the development of downstream processes. “With an effective data and knowledge manage-ment system and the appropriate pro-cesses and experience, the exercise can be straight-forward due to the large amounts of data that already exist on the structure-function relationships for classical large molecule drugs (e.g., monoclonal antibodies). However, more novel structures and platforms will require that the industry expand its knowledge for these types of mol-ecules,” says Studts.

REFERENCES 1. ICH, ICH Q8 R2, Pharmaceutical

Development (ICH, August 2009).

2. L. X. Yu et al., AAPS Journal 16 (4) (July

2014), www.ncbi.nlm.nih.gov/pmc/

articles/PMC4070262/

3. CMC Biotech Working Group,

A-Mab Case Study, www.casss.org/

page/286 X

Downstream Processing — Contin. from page 24


http://www.pharmtech.com/


https://doi.org/10.12665/J16OA

http://www.ncbi.nlm.nih.gov/pmc/

http://www.casss.org/




Data Analytics

From Data to Information Making siloed data accessible across functions and to contract partners is the first step to facilitating continuous improvement

and enabling use of artificial intelligence in manufacturing.

AGNES SHANLEY

Biopharmaceutica l manufacturers have often

described operations as data rich but information

poor. While advanced analytics and sensors collect

more data than ever before, much of it may not be used

or shared with the operations that need it most to prevent

lost batches and quality or compliance problems. The rise

in outsourcing has only intensified the challenge.

IDC Health Insights surveyed 126 biopharmaceutical

and pharmaceutical executives in the United States and

the United Kingdom and found a significant gap between

their need and their strategies for harnessing data (1).

More than 98% of respondents said that cross-functional

data access was important or very important to their busi-

ness strategies, and 94% described the ability to apply

advanced analytics and/or artificial intelligence the same

way. Respondents believed that data access would be cru-

cial to improving overall quality and productivity as well

as the return on investment of their R&D investments.

However, 51% of those surveyed said that they did not

have a clear strategy in place to help them reach either

of those goals, citing regulatory uncertainty, budget pri-

oritization, and the need for more action from functional

operational groups. As Kevin Julian, senior managing

director in Accenture’s Life Sciences practice, the survey’s

sponsor, commented, “Important insights that could lead

to the discovery, development, and delivery of promising

new treatments are too often trapped within the func-

tional silos of ... biotechnology companies” (2).

While some pharmaceutical manufacturers are still

using paper-based record systems, a growing number are

digitizing processes and making more data accessible

in the right context. On a fundamental level, open con-

trol systems and a common data structure have helped

allow this to happen, according to Rockwell Automation,

resulting in distributed control systems (DCS) that

enable integration using unmodified Ethernet, and allow-

ing two-way communication between enterprise resource

planning (ERP) and manufacturing execution systems

(MES) (3).

Work is underway to improve collaboration in pre-

clinical and quality labs, where good laboratory prac-

tices (GLPs), rather than good manufacturing practices

(GMPs), drive operations (see Sidebar) Much progress

is being made in the area of batch records, and expanding Imag

e c

ou

rte

sy o

f A

pp

ren

tice

.io




Data Analytics

GLPs: Better data access needed to improve compliance

Like many crucial regulations, good laboratory practices

(GLPs) were enacted in 1979 after FDA observers found

serious problems in documentation, training, and data

integrity at a number of US research labs (1). Decades

later, regulators still find deficiencies in the way that some

companies’ labs approach data integrity, training, and

standard operating procedures (SOPs).Another major problem that can be traced to GLPs is

reproducibility. According to the Global Biological Standards Institute (GBSI), 50% of published preclinical research cannot be reproduced, a problem that results in product development delays and wastes $28 billion/year in the US alone (2). Culprits were found to be biological reagents and reference materials, study data, and lab protocols.

A number of tools are being developed to help lab scientists capture and use more data, for example, LabStep, an interactive digital platform designed to help scientists get around some of the deficiencies of electronic lab notebooks (ELNs) and refer directly to protocols, SOPs, and other important data (3). LabTwin is introducing a new voice-activated lab assistant at BIO 2019 in Philadelphia in June. Combining artificial intelligence, voice recognition, and machine language, the hands-free device allows researchers to document steps taken and save explicit details that cannot currently be saved in ELNs (4).

Ultimately, compliance depends on following best

practices. Stuart Jones, regulatory quality assurance

professional in good laboratory practice (RQAP-GLP)

and director of quality assurance at PPD Laboratories’

Bioanalytical Laboratory shared recommendations with


BioPharm: What are GLP’s biggest challenges?

Jones: Because we work in such a regulated

environment, a seemingly minor matter can have

a significant impact on quality. As such, training is an

important best practice, from the time of hire, to retraining

when a deviation occurs. Annual refresher training as

well as specific group remedial training also should be

provided when needed. Meanwhile, the use of automated

or electronic systems, such as ELNs, can be especially

beneficial in maintaining the most accurate documentation.

BioPharm: How do you recommend that companies

tackle training?

Jones: Initial training, especially with newer employees,

can be done through reading, lecture, and/or some type of

knowledge or learning assessment, but the best results occur

when that theoretical work is followed up and supplemented

by hands-on training. This is accomplished most effectively

by teaming new employees with experienced staff using

training goals established within a predetermined curriculum.

Some measure of refresher training should be required on

at least an annual basis and it should be consistent across

all experience levels. Metrics generated around unplanned

protocol and SOP deviations, as well as human error,

should be used as indicators in determining the course and

effectiveness of current training plans.BioPharm: What best practices do you recommend to

make data less siloed and more accessible to those who may need it (on cross functional teams?)

Jones: One of the best ways to establish a more cross-functional approach and enhance data accessibility is to use one system across all sites. If one across-the-board system is not a possibility, then the multiple systems must be able to work in tandem. Data portals and SharePoint sites also can be utilized to securely share information on a real-time basis.

BioPharm: Reproducibility is a major problem for preclinical research. Is that also the case for quality control labs? What best practices do you recommend?

Jones: We have found that, after research and development of the method by our scientists, it is important to involve the sample analysis team in performing some, if not all, of the validation experiments, with technical assistance provided, as needed, by the R&D scientists who

developed the method. This approach allows for a shared

collaboration between the research and production teams,

and continues into sample analysis to ensure reproducible

results from the developed and validated method. Best

practices include following the proper bioanalytical method

validation guidances, the bridging of critical reagents,

analyst method qualification, and scientific expertise/

knowledge of the assay, as well as the use of incurred

sample reproducibility testing as one of the bioanalytical

lab’s means of proving the method can be reproduced.

References

1.H. Danan, Pharmaceutical Technology 15(6) (2003).

2. L.Freedman et al, BioPharm International 28(10) pp 14-21 (2015).

3. Lab Twin, “Voice Activated Laboratory Assistant to Launch at BIO

2019,” Press Release, www. scrip.pharmaintelligence.informa.com/

SC125243/LabTwin-Voice-Activated-Lab-Assistant-To-Launch-At-Bio

4. J. Gould, “How Technology Can Help Solve Science’s

Reproducibility Crisis,” nature.com, April 25, 2019, www.

n a t u r e . c o m / a r t i c l e s / d 4 1 5 8 6 - 0 1 9 - 0 1 3 3 3 - 0 # M O 0 .

— Agnes Shanley


http://www.scrip.pharmaintelligence.informa.com/

http://www.na



Data Analytics

connections between electronic lab

notebooks, laboratory information

management systems, MES, and

ERP to increase access to informa-

tion. Augmented reality offers one

way to do this at the basic data

recording and recovery level.

In addition, according to Emerson

Process Management’s consultant

Johan Zebib, quality review man-

agement and review by exception

are being used with MES (4). Data

historians can also be developed as

a point of access, a concept that Eli

Lilly has leveraged with its contract

manufacturers in medical devices (5).

Vendors are offering tools that make

this task easier, with applications that

use machine learning and other fac-

ets of artificial intelligence, allowing

users to make connections between

data points that might otherwise

have seemed unrelated.

AUGMENTED BATCH RECORDS Apprentice.io has developed aug-

mented reality and database applica-

tions that allow users to get feedback

as they perform their jobs and to

compare equipment performance and

different batch runs (6). Contract

development and manufacturing

organizations (CDMOs) are becom-

ing a more important market for

the technology, says CEO Angelo

Stracquatanio, using it not only to

share data, but for training and trou-

bleshooting in real time. “There are

so many silos within manufacturing,

and data are not being leveraged at

different levels,” he says.

In 2019, the company has made

improvements to its augmented

reality products with augmented

batch recordkeeping products that

extend batch connectivity to labo-

ratory information systems (LIMS)

and electronic lab notebooks (ELNs),

allowing inputs to be captured for

every batch. Users can analyze pro-

cess data to compare batch runs and

implement continuous improvement

programs and analyze specific runs to

isolate deviations, Stracquatanio says,

leaving an audit train of data that can

be mined to decrease variability.

A growing number of CDMOs

are using Apprentice.io’s Tandem

remote telepresence tool to col-

laborate with their clients. The

Apprentice System also collects voice,

picture, and other types of data to

create a rich audit trail. “For exam-

ple, for a single-use filter, one can

scan its bar code. Users now know

what filter that is and can create

an audit trail for it … and put data

together in real time, using a hier-

archy of importance to present data

in a way that doesn’t overwhelm the

user.” says Stracquatanio.

ARTIFICIAL INTELLIGENCEMachine learning and artif icial

intelligence are also moving into

pharmaceutical manufacturing appli-

cations. The technology is farther

along in clinical trials and in discov-

ery. Accenture launched INTIENT

in May 2019 to focus on discov-

ery, clinical, and pharmacovigilance

applications. Amgen has been work-

ing with Tata Consultancy Services

on a Holistic Lab digital platform

using Dassault Systemes’ BIOVIA,

for process development (7).

However , some vendor s a re

focusing on pharmaceutical manu-

facturing. Quartic.ai, for example,

has launched an AI-driven plat-

form to provide feedback to opera-

tors and to monitor and improve

processes (8). The platform, which

includes a data engine, designed

to extract data from DCS, quality

management systems (QMS), and

data historians, as well as a connec-

tor that allows disparate software

systems to communicate with each

other, was designed to be integrated

into existing plants and equipment,

but Quartic is also working with

a pharma company to embed the

platform into a new facility.

Quartic.ai cofounder and CEO

Rajiv Anand has an extensive auto-

mation and reliability background

and previously worked at Emerson.

The company’s management team

members all come from pharmaceu-

tical and automation backgrounds.

“We didn’t want pharma users to feel

that they needed to be coders or data

scientists,” says vice-president of life

sciences Larry Taber

Although use of

artificial intelligence

is more advanced in

clinical, discovery,

and research

applications,

new platforms

are targeting

manufacturing.

Once deployed,

machine learning

models could ...

predict potential

failures ... to trace

the source of

the failure down

to an individual

component.




Data Analytics

LEVELS OF DIGITAL MATURITYThe platform is geared to the fact

that every potential user will have

a different level of digital matu-

rity, says Anand. Once legacy data

sources have been connected, the

artificial intelligence engine can be

used to solve a specific problem (e.g.,

monitoring an asset’s performance

for deviations), he adds. Some clients

are using it for complex predictive

work (Photo, above, shows the plat-

form in use at a biopharm facility).

The company has applied the

platform in a number of s i tua-

tions, including an effort to monitor

and improve fermentation yield in

a highly variable process where all

critical quality attributes were under

control. Quartic extracted data and

identified a few key batches, Anand

explains, and then built an algorithm

to study relationships between the

batches, clarifying eight years’ worth

of data and fingerprinting each

phase of the process. Ultimately pre-

viously unknown sources of varia-

tion were discovered. Work will now

focus on learning more about them .

The company has also done work

with predictive maintenance. Anand

recalls one project designed to baseline

the performance of an autoclave. The

equipment was modeled and industrial

Internet of Things (IIoT) sensors used

to get additional vibrational and ultra-

sound information. Once deployed,

machine learning models could then

predict potential failures with the abil-

ity to trace the source of the failure

down to an individual component (i.e.,

a damaged valve).

There are many other applications

where artificial intelligence could be

applied to pharmaceutical manufac-

turing operations, particularly in visu-

alizing end-to-end processes. As data

analyst Jonathan Lowe (9) found at

one company, more than 100 quality

events were being investigated at any

one time, stretching staff capacity. A

machine learning model was designed

to predict which events would take

the longest to resolve. The model

predicted more than 85% of the

severe delays weeks before they hap-

pened, allowing quality managers to

prioritize tasks more equitably.

REFERENCES1. Accenture, “The Case for

Connectivity in the Life Sciences,”

Infographic, accenture.com, ,

May 22, 2019, www.accenture.

com/_acnmedia/PDF-101/Accenture-

INTIENT-Infographic-IDC.pdf.

2. Accenture, “Accenture Introduces

Intient,” Press Release, accenture.com, ,

May 16, 2019,www.newsroom.accenture.

com/news/accenture-introduces-

intient-an-innovative-platform-to-

advance-the-discovery-development-

and-delivery-of-patient-treatments.htm.

3. B. Sisk, “Analytics Informs

Decisions in the Facility of the

Future,” a Rockwell automation

white paper to be published in

July 2019 on pharmtech.com.

4. J. Zebib, “Review by Exception:

Connecting the Dots,” an

Emerson Process Management

white paper to be published in

July 2019 on pharmtech.com:

5. D. Berg et al., “Data Sharing

in a Contract Manufacturing

Environment,” a presentation at

the OSI Soft Users Conference,

2017, osisoft.com, www.cdn.osisoft.

com/osi/presentations/2017-uc-

sanfrancisco/UC17NA02LS04_EliLilly

BGoldingerAPadillaDBergCMoore_

Data Sharingina Contract

Manufacturing Environment_

fordistribution.pdf?_ga=2.254688200.

1912970547.158360174-

1538190911.1557339846

6. A. Shanley, “Mixed Reality Gains

a Foothold in the Lab,” Biopharm

Lab Best Practices ebook issue 2,

pp 8-9, pharmtech.com, November

15, 2018, www.pharmtech.com/

mixed-reality-gains-foothold-lab

7. A. Louie, “Empowering 21st Century

Science in Life Sciences,” an IDC

Perspectives Paper, Document

VS43749317, idc.com, May

2018, www.idc.com/getdoc.

jsp?containerId=US43749317

8. F. Marizol, “Quartic Introduces AI

Platform for Process Manufacturing

Operations at INTERPHEX

2019, biopharminternational.

com, www.biopharminternational.

com/quarticai-introduces-ai-

platform-process-manufacturing-

operations-interphex-2019

9. J W. Lowe, “Why Biopharma

Manufacturing Needs to Leverage

Network Optimization Techniques

via Data Science,” medium.com,

June 19, 2018, www.medium.com/

bcggamma/why-biopharma-

manufacturing-needs-to-leverage-

network-optimization-techniques-

via-data-science-ffe6e1bb5ee3 ◆ Imag

e c

ou

rte

sy o

f Q

uart

ic.a

i


http://www.accenture

http://www.newsroom.accenture

http://www.cdn.osisoft


http://www.idc.com/getdoc

http://www.biopharminternational

http://www.medium.com/



Operations

Moving PAT from Concept to RealityThe learning curve for process analytical technology

has slowed widespread adoption.

CYNTHIA A. CHALLENER

Process analytical technology (PAT) is applied in

the biopharmaceutical industry for analysis of raw

materials, in-process monitoring, and final product

analysis. PAT is not only enabling, but essential, to con-

tinuous bioprocessing. With sufficient advances, emerging

PAT solutions should ultimately make real-time release

testing possible.

IN-LINE, AT-LINE, AND ON-LINETo understand the state of PAT technology development,

it is necessary to understand the different types of PAT

operations used in biologics manufacturing. In-line sen-

sors are placed in a process vessel or process stream to

conduct the analysis in-situ. On-line sensors are connected

to process side streams and perform periodic automatic

sampling, returning fluid back to the process streams

after analysis is complete. At-line—or off-line—analy-

ses involve collection of a sample from the process, with

analysis performed away from the process. In-line and on-

line sensors allow for continuous process measurement and

control, while at-line measurements cause a delay between

sampling and availability of the results, preventing their

use for direct process control.

STILL ON THE LEARNING CURVEThe biopharmaceutical industry and regulatory agencies

have recognized the value of PAT. Although many large

multinational manufacturers have adopted and implemented

various forms of PAT, many companies are still struggling to

get started, according to Joe Makowiecki, enterprise solution

architect with GE Healthcare.

“Despite the fact that the concept is supported by most

scientists, implementation is limited at commercial manu-

facturing sites. Adoption of PAT is certainly not progress-

ing as fast as was expected 16 years ago,” asserts Moheb M.

Nasr, principal consultant with Nasr Pharma Regulatory

Consulting. “While we [have seen] an increase in the inter-

est in and value perception of PAT among our customers

within the last two to five years, we believe that its full

potential is not yet being used,” agrees Svea Grieb, product

manager for PAT at Sartorius Stedim Biotech.

In many cases, Makowiecki adds, reliable, low cost, on-

line/at-line analytical sensors needed for the measurement of

ale

xlm

x a-

Sto

ck.A

do

be

.co

m

CYNTHIA A. CHALLENER, PHD, is a contributing editor to





Operations

critical product quality attributes and

product-related species are not com-

mercially available. An additional chal-

lenge is the development of sensor/

detector/measuring technologies that

allow for PAT in the single-use space.

For companies that have adopted

PAT, these tools are applied for

raw material analysis and monitor-

ing/control of process performance,

according to Arpan Mukherjee, tech-

nical committee coordinator for the

National Institute for Innovation in

Manufacturing Biopharmaceuticals

(NIIMBL). Raw-material character-

ization is performed using handheld

Raman/near infrared (NIR) scanners.

In bioreactors, in-line sensors measure

pH, temperature, dissolved oxygen

(DO), and carbon dioxide; in-line opti-

cal sensors (Raman, NIR) are coupled

with multivariate modeling to mea-

sure metabolites. In addition, a variety

of on-line tools measure cell density

(dielectric spectroscopy, fluorescence

spectroscopy); protein aggregates

(size-exclusion chromatography and

ultra-high-performance liquid chroma-

tography [UHPLC]); product concen-

tration (HPLC); and protein charge

variants (ion exchange chromatography).

Numerous at-line analyses evaluate host

cell proteins (HCPs), DNA, viable cell

density, bioburden, aggregates, product

concentration, and particulates.

One of the greatest difficulties with

many current at-line methods is the

extended length of time required to

receive results—for instance, 28 days

for most cell-based assays. The focus of

research in these areas is the development

of rapid methods that are sufficiently

accurate and robust to allow adoption.

UPSTREAM FOCUSMost PAT tools that find wide use

today are designed for application

in upstream processes. “This focus

is in large part due to the fact that

initial protein quality and effective-

ness are established during cell cul-

ture or fermentation. Changes in the

bioreactor conditions during protein

production will impact all down-

stream processes. In addition, the

largest number of sensor technologies

available for use in biologics manu-

facturing are designed for upstream

applications,” says Richard D. Braatz,

Edwin R. Gilliland professor at the

Massachusetts Institute of Technology

(MIT). “Trace metals, glucose, lactate,

pH, DO, amino acid content, glyco-

sylation profiles, and HCPs must be

measured to monitor the process and

enable feedback/feedforward control

to optimize yield (in-line and on-line

only for control),” Mukherjee observes.

The challenge with downstream

unit operations is partly the lack of

obvious opportunities for using sen-

sors, Braatz notes. In column chroma-

tography, for instance, analysis cannot

be performed until after the column,

preventing any in-process monitoring.

The diversity of downstream processes

is also a consideration. “Not only are

there many possible downstream unit

operations, but also the critical qual-

ity attribute (CQA) most impacted

by each step is diverse. The traditional

methods for quality attribute measure-

ment are also often product-specific,”

says Makowiecki. As a result, the

diversity of downstream processing

design makes it difficult to develop a

universal set of technologies that will

cover all of downstream processing

for all molecules and their associated

quality metrics.

Next-generation therapies are cre-

ating additional opportunities for

PAT adoption, though. In personal-

ized medicines such as autologous cell

therapies, for instance, the nature of

the treatment demands a process that

is flexible and can dynamically adjust

to wide variations in starting material,

according to Grieb. PAT can account

for the variations and peculiarities of

the cells from different patients in an

automated fashion, enabling a high

process consistency irrespective of the

starting material.

PAT can also help overcome the

analytical challenges presented by viral

vectors for novel vaccines and gene

therapies. These products are not well-

characterized molecules like monoclo-

nal antibodies, but a complex of various

proteins, DNA/RNA, and in some cases

lipid membranes. “This complexity

makes it hard to identify and under-

stand the factors influencing the product

CQAs. Hence, these processes benefit

from a stricter control strategy, where

high levels of automation and imple-

mentation of PAT and advanced data

analytics play a key role,” Grieb asserts.

ESSENTIAL FOR CONTINUOUS MANUFACTURINGProcess intensification/continuous

bioprocessing is a hot topic in the

biopharma industry at the moment

because it enables increased produc-

tivity of single-use facilities while

decreasing the footprint. It also brings

incentives to invest in PAT, and

advances in sensor technology/connec-

tivity will make continuous processing

possible, according Makowiecki.

Intensified processes are much

more complex than conventional fed-

batch processes and therefore require

tighter monitoring and control, adds

Grieb. “PAT and automation do not

only provide this, but also reduce

the complexity for the operator,” she

says. In Nasr’s view, PAT is critical

for achieving the enhanced controls

required to ensure quality through-

out the entire batch during operation

of continuous processes. “Regulators

expect process monitoring and con-

trols based on the entire batch data

and the ability to revise controls to

compensate for raw material variabil-

ity or the use of different batches of

raw materials,” he observes. In addi-

tion to in-line process control, there is

also a need for advanced in-line PAT

for continuous/hybrid batch manu-

facturing to enable real-time batch

release, according to Mukherjee.




Operations

MANY DRIVERS FOR ADDITIONAL DEVELOPMENTOne of the biggest advantages to using

PAT and biopharmaceutical manufac-

turing is the increased process under-

standing that is gained, which leads

to more consistent product quality,

according to Ruben Carbonell, chief

technology officer for NIIMBL. It

also allows for increased productiv-

ity, connectivity, and automation, says

Makowiecki. Reducing the need for

manual sampling lowers the risk of

operator error and contamination,

while the timely identification and

correction of process irregularities will

help minimize the risk of lost batches,

Grieb notes.

Furthermore, asserts Grieb, a well-

characterized and monitored process

together with scalable hardware can

significantly reduce the cost and efforts

of process scale-up and scale-down.

Overall, therefore, PAT contributes to

acceleration of process development

timelines for reduced time to market,

concludes Carbonell.

PAT should also ultimately make

real-time product release possible.

“PAT is bringing quality control

testing closer to the manufacturing

floor for on-time/real-time release

and development of predictive mod-

els to enable active process control

and reduce batch rejection rates,”

Makowiecki asser ts . “Real-t ime

release is important for reducing the

time to market. Instead of sitting

on a shelf in storage for up to sev-

eral months, medicines can be put in

the hands of patients very quickly if

real-time release is possible,” Braatz

states.

Speeding drug development is cru-

cial given that many drugs in clinical

trials fail to reach the market. Drug

companies would like to start manu-

facturing process development later in

the overall development cycle—prefer-

ably during Phase III of clinical trials—

in order to focus their investments on

candidates that have the greatest likeli-

hood of obtaining regulatory approval.

By reducing process development

timelines, PAT is making it possible

for companies to take this approach,

which saves time, money, and effort,

according to Braatz.

On a similar note, advanced PAT

solutions often serve as better meth-

ods for advanced process develop-

ment. They allow for monitoring of

processes and product attributes that

can provide the most optimal can-

didates to take forward in terms of

quality attributes and productivity,

according to Stacy L. Springs, execu-

tive director of the Biomanufacturing

Program at MIT.

Braatz adds that PAT provides

increased production f lexibi l i ty.

“There is a lot of uncertainty about

the market size when drugs are in

development; the actual demand will

depend on whether a drug reaches the

market first before other competitors

and how accurate predictions of the

user base are. The more information

that a company has about its processes,

the better decisions it can make, such

as about whether to scale up in single-

use or stainless-steel equipment,” he

explains.

BUT BARRIERS TO ADOPTION REMAINWhile PAT implementation affords

many benefits, there also exist many

hurdles that must be overcome before

it becomes widely adopted across

the biopharmaceutical industry. Cost

is certainly an issue. So is the lack of

experience and experts with training

in advanced analytics and modeling,

according to Nasr.

There are regulatory challenges as

well, says Grieb. “Some concepts of

modern automation technologies and

sensor technologies are not yet cov-

ered by regulatory guidelines, particu-

larly those used for multivariate data

analysis, which takes all available data

and integrates them into a fingerprint.

The adoption of such batch-finger-

printing concepts must be considered

by the regulatory bodies.” The same

questions arise for multi-analyte sen-

sors that are based on computational

models, which is the case for spectros-

copy, for example, she adds. The risk of

delay to a filing application can result

in the lack of a business case, accord-

ing to Carbonell. The complex regula-

tory framework around the world also

creates risk aversion.

Certain information technology

questions remain, too, Grieb notes. A

comprehensive automation strategy for

an entire bioprocess, and potentially an

entire production site, requires connec-

tivity of all components and a central-

ized control unit. “That would require

data sharing and access that implies

safety risks. We experience reluctance

among our customers to adopt new

technologies such as cloud computing

and wireless communication of PAT

components,” she explains.

On a more basic level, Carbonell

adds that there is often lack of con-

fidence in testing robustness and

integrity testing. In addition, lack

of thorough process understanding

can lead to ambiguity regarding the

attributes that should be measured.

This barrier is readily evident with

The diversity of

downstream

processing design

makes it difficult to

develop a universal

set of technologies

that will cover all

downstream

processing for

all molecules.




Operations

the lack of integration into the exist-

ing process equipment installed base,

automation platforms, and control

strategies, adds Makowiecki. He also

comments that the ability to identify

the right opportunities to implement

PAT without causing commercial-

ization delays or rework, the need to

design in PAT solutions through pro-

cess development stages, and to really

validate them during scale-up pre-

vents adoption.

For continuous bioprocessing in

particular, the lack of experience with

PAT at commercial sites that have

typically performed batch processing

combined with the perceived business

and regulatory risks of implement-

ing new technologies are hindering

PAT implementation, according to

Nasr. “The lack of availability and

reliability of cost-effective in-line/on-

line analytical sensors needed for the

measurement of CQAs and product-

related species is one of the gaps in

continuous processing, but with many

companies evaluating continuous pro-

cessing, there is also synergy to explore

PAT as an enabler,” adds Makowiecki.

Sartorius also thinks intensified/con-

tinuous processing will boost novel

PAT solutions, because as companies

establish new manufacturing pipelines

with unique requirements, they can

justify the costs and efforts of going

through the approval for commercial

manufacturing.

TECHNOLOGY GAPS TO BE ADDRESSEDOverall, there needs to be a standard

path to implementation for PAT, with

technology available that fits each

application and does so across all

manufacturing scales and a practical

approach to connectivity, according to

Makowiecki. A higher degree of auto-

mation for upstream bioprocesses and

standardization of the process steps

would lead to improved batch-to-batch

consistency, and in turn, product quality,

Grieb agrees.

Grieb also notes that, while most

PAT implementation has targeted

upstream processes, there are plenty of

examples where PAT could significantly

improve downstream processes as well.

Examples are automated venting of fil-

ters and protein quantification during

column loading. “We expect to see more

downstream targeted PAT implementa-

tion within the next years,” she says. In

particular, Springs points to a need for

low-cost, robust, downstream PAT solu-

tions that are non-invasive and do not

require advanced interfaces with equip-

ment, which can impact sterility.

There are also specific sensor tech-

nologies that need improvement

or have yet to be developed, accord-

ing to Kelvin Lee, NIIMBL’s direc-

tor. Examples include high-resolution,

specific, robust PAT tools with a low

limit of detection and in-line, reus-

able sensors with high frequency

measurements that do not require cali-

bration over the course of the batch.

The ability to characterize proteins in a

bioreactor on-line via a reliable, repro-

ducible, rugged, high-precision, and

high-throughput liquid chromatog-

raphy–mass spectrometry (LC–MS)

instrument at a cost of $300,000 rather

than $1.3 million would be a game-

changer, asserts Braatz.

Although a difficult problem to solve,

sensors that rapidly measure viral and

microbial contamination are needed

the most, Braatz states. The long (28-

day) time to receive results from cell-

culture-based sterility tests could delay

product release when needed, espe-

cially for vaccines or autologous cell

therapies like chimeric antigen recep-

tor (CAR) T. That is why application

of rapid methods and next-generation

sequencing for sterility testing is creat-

ing so much excitement, adds Springs.

As importantly, if contamination is

caught sooner using in-process rapid

testing for virus or microbes, contami-

nation can be stopped before spreading

downstream in the process, saving both

money and time.

EMERGING TECH IS EXCITINGMany PAT technologies are under

development in both academia and

industry. Braatz and collaborators

at MIT and Biogen conducted an

18-month study to identify different

technologies in use and in develop-

ment for a wide range of CQAs and

classified them according to the time-

frame in which they were likely to be

adopted (1).

Some of the promising emerg-

ing PAT solutions include slanted

nano-arrays and spectral analysis

with partial least squares for protein

aggregates; microfluidic technol-

ogy for analysis of post-translational

modifications and sequence variants;

nanotechnology-based analysis of

charge heterogeneity that does not

require protein purification; aptamer-

based biosensors for N-glycosylation

evaluation; next-generation sequenc-

ing (NGS) for viral and microbial

contamination quantification; surface

plasmon resonance, amplified lumi-

nescent proximity homogeneous assay,

and fluorescence resonance energy

transfer for target and Fc binding

analysis; liquid chromatography cou-

pled with ultraviolet, fluorescence, or

MS detectors for evaluation of pro-

cess-related impurities; and variable

pathlength spectroscopy solutions for

protein concentration measurement in

real time (1).

Microfluidic devices and contact-

free PAT technologies are among

the most recent advances but are still

mostly in the laboratory proof-of-

concept stages, according to Carbonell.

“Microfluidics-based analyzers require

a small sample volume and provide

higher resolution than existing PAT

technologies,” he explains. He points

to three additional microfluidics tech-

nologies—particle analyzers for on-

line protein aggregation detection

and monitoring, devices for on-line

or at-line detection of adventitious

agents, capillary electrophoresis and




Operations

capillary isoelectric focusing-based

microfluidics devices for real-time

protein analytics—and MS-integrated

microfluidics.

“These technologies are currently

being evaluated by the biopharma

industry and are in different phases of

development (alpha and beta testing).

They have the potential of increas-

ing process/product knowledge, early

detection of contaminants, and reduc-

ing the need for comprehensive end-

point quality testing,” Carbonell says.

Spectroscopic methods (both

Raman and NIR) are currently

deployed but are not yet widely

adopted, according to Makowiecki.

Sartorius Stedim Biotech also believes

that spectroscopic techniques will

become more abundant in both

upstream and downstream biopro-

cessing, due to its capability of label-

free, online measurements of several

analytes, cell properties, and product

quality attributes. “Spectroscopy has

the potential to replace offline mea-

surements during the bioprocess. We

envision the use of a combination of

different spectroscopic techniques—

such as NIR, Raman, and UV-Vis—to

be required for this,” says Grieb.

Soft sensing (transforming existing

signals and leveraging advanced process

understanding to infer/gain visibility

to an attribute without direct measure-

ment) is making it possible to moni-

tor/predict performance through use

of surrogates, according to Makowiecki.

“As a result, the industry doesn’t have to

wait for sensor maturity for CQAs to

begin their PAT journey,” he says.

COMMERCIAL IMPACTSThe application of sophisticated PAT

tools in combination with multivari-

ate data analytics is starting to have a

high impact on commercial processing,

according to Grieb. “Measurements

are moving forward in the process

to the point of controllability. Using

process fingerprints, the state of the

process can be assessed at any time.

Furthermore, through real-time uni-

variate and multivariate process moni-

toring, data can be used for simulation

and modeling of process design and

control and ultimately lead to prescrip-

tive analytics for product quality,” she

explains. In the near future, Sartorius

Stedim Biotech also expects wider

spread adoption of analytics in GMP

that are already available, such as spec-

troscopy for metabolite control and

bio-capacitance for viable biomass.

Braatz is looking forward when cost

of LC–MS systems is reduced suf-

ficiently to allow widespread adoption

for real-time monitoring of biopro-

cesses. He notes that few people in

the 1980s would have expected power-

ful, easy-to-use, small-sized LC–MS

systems to be hundreds of thousands

of dollars, so development is on the

right trajectory. NGS technologies are

also very promising. “Next-generation

sequencing could be very helpful as it

is applied to more advanced and com-

plex therapies, such as genome-edited

products,” Springs asserts.

Springs adds that some of the tech-

nologies being developed to measure

the sterility of autologous cell therapies

should be applicable to traditional bio-

logics. “We may see more innovation

in the cell-therapy space first,” she says.

Overall, Braatz believes that PAT

development has reached a point

where there have been sufficient

advances that have resulted in real

improvements in analytical capabilities

that the concept of real-time-release

testing can be realistically considered.

“We are getting to a very exciting place

now,” he says.

COLLABORATION IS NEEDEDIncreased adoption of PAT will be

driven by regulatory clarity and sup-

port, industry collaboration, advance-

ments in connectivity and technology,

the introduction of PAT-focused

platforms and services by vendors,

and further implementation of con-

tinuous processing, according to

Makowiecki.

Emerging technologies are prom-

ising, but appropriate software and

hardware development is necessary

for integration into existing biopro-

cesses and for automation, especially

for continuous/semi-continuous pro-

cesses, notes Lee. “The coupling of

these technologies with new automa-

tion systems is likely to dominate the

future of biopharmaceutical manu-

facturing. A key challenge is the need

to de-risk the adoption and imple-

mentation of these technologies in

a highly regulated environment. We

believe that public-private partner-

ships that enable multiple stakeholders

to innovate collaboratively provide the

opportunity to de-risk such advances,”

he states.

“It is essential to reduce the techni-

cal risk of emerging PAT solutions,

especially as the industry moves

toward real-time feedback control and

scales out the manufacturing of autol-

ogous cell therapy products,” accord-

ing to Springs. “By working together,

we can find the best solutions that

allow medicines to get to the patients

faster,” she concludes.

REFERENCE1. M. Jiang, et. al., Biotechnology

and Bioengineering, 114 (11) 2445–2456 (2017). ◆

A standard path to

implementation

for PAT—with

technology that fits

each application and

across all

manufacturing

scales—is needed.FOR PERSONAL, NON-COMMERCIAL USE



Supply Chain

On the Right TrackProactive approaches that consider long-term supply chain security

compliance are recommended to ensure companies stay on the right track.

FELICITY THOMAS

Despite there being various terms used, counter-

feit, falsified, fake, and so on, a drug that has

been fraudulently manufactured and distributed

to mimic an authorized medicine, whether branded

or generic, poses significant risks to companies and,

more importantly, to patient health. The World Health

Organization (WHO) estimates that one in 10 medical

products are substandard or falsified in low- to middle-

income countries, based on a literature review of previ-

ously published papers (1).

In f inancia l terms, as repor ted by S trateg y&,

PricewaterhouseCoopers’ strategy consulting business,

falsified medicines represent a lucrative proportion of

illicit goods sold within the global market, estimated to

range from €150 billion to €200 billion (US$163 billion

to $217 billion) per year (2). Given the size of the mar-

ket and the risk to patient health, many authorities have

been implementing regulations to protect the security of

the supply chain.

“The proliferation of online pharmacies, and the

Internet in general, has meant that the pharmaceutical

black-market has trickled into mainstream society and

consequently become a widespread issue,” asserts Staffan

Widengren, director corporate projects, Recipharm. “As

a result, health regulators have established new legisla-

tion and surveillance strategies around supply chains in

a bid to prevent and minimize the circulation of falsi-

fied drugs. Without supply chain security measures, we

cannot effectively track or determine the legitimacy of a

drug product.”

“Supply chain security is a core end-to-end capabil-

ity in a business to ensure that all products reaching

the patient are safe, compliant, and delivered on time

and in full,” adds Roddy Martin, chief digital strategist,

TraceLink. “Most importantly, the elements of risk and

security are proactively tracked across the end-to-end

business so that any deviations are detected quickly and

responded to, without impacting the continuity of sup-

ply or impacting patient safety.”

Security of the supply chain is critical for all companies

that offer products and services to consumers, concurred

Ettore Cucchetti, CEO of ACG Inspections, particularly

in terms of counterfeit products, product damage or theft,

and smuggling. “For the pharmaceutical industry, which

is dealing with products and services directly impact-

ing human health, supply chain security becomes more Gri

ban

ov

- st

ock

.ad

ob

e.c

om




Supply Chain

crucial in terms of a company’s prod-

uct integrity, brand image, and, ulti-

mately, its bottom line,” he says.

DIFFERENT APPROACHESAs Michae l P i s a and Den i s e

McCurdy reported in their policy

paper in February 2019, at a basic

level there are two traceability mod-

els that can be adopted (3). One

model is to have a point-of-dispense

verification approach where verifica-

tion occurs at the top of the supply

chain and then also at the bottom.

The other model is full traceability,

which is more complex in nature as

the tracking and tracing of products

occurs every time they change hands

within the supply chain.

Many countr ies and reg ions

have already signed a traceabil-

ity approach into law, inc luding

China, India, Turkey, the European

Union, and the United States, and

approaches var y f rom countr y-

to-country. “Verification and full

traceability can both facilitate and

improve supply chain secur i t y, ”

says Widengren.

The EU and US, fo r exam-

ple , chose the adopt d i f fe rent

approaches. The former employ-

ing the point-of-dispense verifica-

tion approach, while the latter is

using the full traceability approach.

“In the EU market, serialization

requirements were implemented

as part of the falsified medicines

directive (FMD) regulation to pro-

tect the safety of patients,” adds

Widengren. “Essentially, through

serialization, dispensers gain the

ability to verify product legitimacy

before a drug reaches the patient

by scanning the unique identifier

included on the pack.

“Whereas, track-and-trace systems

can not only determine the authen-

ticity of a product at the point of

dispense, but also track the move-

ment of products and prohibit fal-

sified medicines from progressing

through the supply chain,” he con-

tinues. “Each partner involved in

getting drugs to market can scan

unique identifiers to access data

around the journey of medicines

and verify the authenticity of medi-

cines as they move through the

supply chain.”

DEALING WITH DATAEach traceability approach being

implemented across the world has

inevitably impacted industry, in par-

ticular as a result of the need to deal

with vast amounts of data. “Due to

the sheer amount of data generated

by serialization requirements, orga-

nizations have been required to eval-

uate and adopt software technology

solutions to create, capture, store,

report, and share compliance data at

scale,” notes Martin. “This question

of technology scalability remains

a real concern when it comes to

simply meeting the requirements

of these legal mandates themselves,

which is one of the critical reasons

that a cloud-based, network plat-

form is optimal,” he continues.

In agreement, Widengren states

that c loud-based networks have

been found to be the most success-

ful in terms of connecting supply

chain partners and enabling the

exchange of serialization data. “As

well as enabling compliance with

serialization regulations, these plat-

forms also offer the opportunity for

businesses to improve supply chain

visibility and gain additional value

from their investment,” he says. “By

giving companies greater insight

into their operations, businesses can

make more informed decisions in

areas such as supply and demand

forecasting, product recalls, and even

achieve engagement with patients.”

Supply chain risk and security maturity evolution

Discussing supply chain risk and security as a business led

journey, Roddy Martin, chief digital strategist at TraceLink,

explains the five stages of its evolution to BioPharm

International:

• “Stage 1. Reacting to risk and security

problems after the fact.

• Stage 2. Specialized security and risk management

projects; for example, track and trace/serialization.

• Stage 3. Supply chain risk and security are a functional

excellence capability; for example, risk and security

requirements are codified into all work within functions

like manufacturing, procurement, logistics, and so on.

• Stage 4. Supply chain and risk are codified as

core “this is how we work” requirements in all

horizontal, end-to-end, and cross-functional

processes from the patient all the way back

through the business into all elements of supply.

• Stage 5. Risk and security capabilities are

embedded into and across the total ecosystem

and network both internal and external to a

company; the core capability is that product

integrity, availability, and patient safety are

regarded as a given. In stage 5, risk and

security are both driven as value based

capabilities rather than seen as a cost.”




Supply Chain

Additionally, Martin emphasizes

that as industry looks to the future

and leveraging the data gained from

serialization, there will be a shift

away from the fragmented silo nature

of the bio/pharma supply chain that

has existed previously as a fractious

supply chain hinders visibility and

impacts performance. “Instead, seri-

alization should be used as a lens to

look at the end-to-end digital supply

chain and, if done right, will lead

to transformative benefits in terms

of increasing business value through

more collaborative supply chains and

end-to-end visibility into value net-

works,” he explains.

“Blockchain will be considered as

one of the critical factors when it

comes to selecting a supply chain

partner in the future,” adds Cucchetti.

“Product traceability and recalls are

known to be the biggest challenges

for most industries, and blockchain

landscape can be used to secure the

transaction between the supply chain

partners. With blockchain, compa-

nies can address counterfeit issues

through the authentication process,

and they can perform product recall

smoothly. This can help them to

identify the issues in logistics and

distribution channels, using the com-

plete supply chain data to optimize

the supply chain.”

REGULATORY INITIATIVES“Regulatory and government bod-

ies are looking into all available and

emerging technologies for secur-

ing supply chains,” notes Cucchetti.

“Each regulatory body has multi-

ple objectives, but the preliminary

goal remains the same—to secure

the product from manufacturer to

end consumer.”

Giving some examples, Cucchetti

highlights Russia, which has man-

dated crypto tail into barcoding pro-

cesses; Indonesia, which is assessing

product authentication techniques;

and the US, which is looking to eval-

uate blockchain with serialization.

“Currently, most of the regulatory

requirements are focused towards

serialization and track and trace, as

well as mandates for the pharma-

ceutical industry,” he says. “Going

forward, it is likely that similar regu-

lations will be applicable to all other

industries as well. Government and

regulatory bodies will be more strin-

gent in regulation—considering con-

sumer health and safety requirements.

As the technologies evolve, each gov-

ernment will be evaluating possible

technological implementations to

secure supply chains to fight against

counterfeiters, and also to have com-

plete visibility of the industry.”

Specifically focusing on the US

and its exploration of methods to

enhance the safety and security

of the supply chain, Martin dis-

cusses FDA’s Drug Supply Chain

Security Act (DSCSA) pilot pro-

gram. “Recently, FDA announced a

pilot program project seeking inno-

vative and emerging approaches

for enhanced tracing and verifica-

tion of prescription drugs in the

US to ensure suspect and illegiti-

mate products do not enter the sup-

ply chain,” he confirms. “TraceLink

was accepted into the pilot program

and will focus on two workstreams;

blockchain and digital recalls.”

Companies of varying sizes will be

included in the TraceLink pilot proj-

ect, covering the end-to-end supply

chain. “Together, through network

connectivity and innovative software

solutions, participants will explore

and collaborate on ways to improve

the safety and security of the drug

supply chain and will use early stage

technology to do so,” Martin adds.

SAFEGUARDING FUTURE SUPPLY CHAINS“Companies should always be mind-

ful of new ways they can safeguard

their supply chains, especially when

the political landscape is in a state

of flux,” emphasizes Widengren. “It

is essential to consider long-term

prospects so that a plan can be made

around new legalities. As such, phar-

maceutical manufacturers should

invest time into understanding the

markets they operate in, as well as

the ones they may potentially pursue.

This way they can design a strategy

that will help facilitate market entry

and progression with as little com-

plexity and limitation possible.”

Fo r C u c c h e t t i , a p ro a c t i v e

approach to supply chain security is

key as it can afford companies time

to be able to adapt to all changes

required when complying with reg-

ulations. “Companies should form

a dedicated team with all business

functions involved in the serializa-

tion project, documenting all reg-

ulatory and business requirements,”

he says. “At all times, organizations

should work alongside the imple-

mentation partner and possibly with

the regulation bodies to understand

the upcoming changes and work

towards accommodating them.”

As a f ina l note , W idengren

explains that for companies to be

able to reap the benefits of supply

chain security requirements and for

optimum preparedness and future

safeguarding, companies should

consider implementing aggrega-

tion capabilities. “Aggregation is not

always a mandatory measure,” he

summarizes, “but it is expected to

become part of legislative require-

ments in the future.”

REFERENCES1. WHO, “A Study on the Public Health

and Socioeconomic Impact of Substandard and Falsified Medical Products,” Report, November 2017.

2. Strategy&, “Fighting Counterfeit Pharmaceuticals New Defenses for an Underestimated—and Growing—Menace,” Report, June 29, 2017.

3. M. Pisa and D. McCurdy, “Improving Global Health Supply Chains Through Traceability,” Center for Global Development Policy Paper 139, February 2019. ◆



June 2019 www.biopharminternational.com BioPharm International 45

Ask the Expert — Contin. from page 46

Regulatory Beat

New Technology Showcase

The most important and critical element for OOS inves-

tigations is specifying the timeliness. This should be stipu-

lated in the SOP and, in most cases, the investigation into

the OOS, from the laboratory perspective, should be con-

cluded in 24 hours or less. The expectation of when the

contract lab will inform you of any OOS obtained should

be clearly defined in your quality agreement. The sooner

a laboratory error can be ruled out as the cause of the OOS

result, the sooner the investigation can be started.

Taking the time to establish a quality agreement and

investigate the details of their OOS procedure is the first

step in establishing a good working relationship with

your contract test laboratory. The final product testing

procedure for OOSs isn’t the only one you need to review,

however. You should also look at the quality agreement

and OOS procedure being used by your manufacturer for

in-process test results, assuming they are different entities.

The same information required in the final product OOS

procedure should be the same for in-process testing.

REFERENCES 1. 21 CFR 200.10 (b)

2. FDA, Contract Manufacturing Arrangements for Drugs: Quality

Arrangements: Guidance for Industry (FDA, November 2016).

3. European Commission, The Rules Governing Medicinal Products in the

European Union, Volume 4, EU Guidelines for Good Manufacturing

Practice for Medicinal Products for Human and Veterinary Use,

Chapter 7, Outsourced Activities (EC, January 31, 2013).

4. EC, EudraLex, The Rules Governing Medicinal Products in the European

Union, Volume 4, EU Guidelines for Good Manufacturing Practice for

Medicinal Products for Human and Veterinary Use, Part 1, Chapter 6:

Quality Control (EC, October 2014).

5. EC, EudraLex, Volume 4, Good Manufacturing Practice, Medicinal

Products for Human and Veterinary Use, Part II: Basic Requirements

for Active Substances used as Starting Materials (EC, September

2014).

6. FDA, Guidance for Industry, Investigating Out-of-Specification (OOS)

Test Results for Pharmaceutical Production (FDA, October 2006). ◆

Ad Index

Company PageBINSWANGER MANAGEMENT CORP 2

CATALENT PHARMA SOLUTIONS 48

CYGNUS TECHNOLOGIES 15, 21

LABVANTAGE SOLUTIONS, INC 47

MASTER CONTROL SYSTEMS 7

PDA 11

PDA EUROPE 17

US PHARMACOPEIAL CONVENTION 5

WATERS CORP 25

INVESTMENT IN INTEGRATED BIOLOGICS DEVELOPMENTCatalent Biologics provides

advanced technologies and tailored solutions for biologic development

from DNA to commercial supply. Catalent recently commenced a

$200-million investment to expand drug substance and drug product

manufacturing capacity at its Madison, WI and Bloomington, IN sites.

The expansions were in response to increasing demand from existing

and future customers following the company’s 30th commercial product

approval. Catalent, 14 Schoolhouse Road, Somerset, NJ 08873 USA,

tel: +1.888.765.8846, [email protected], www.catalent.com

NGC PLATFORMThe NGC platform has evolved to

meet the changing requirements of

chromatographers and now includes

ChromLab Software version 6.0 to address

the needs of high-throughput labs with

features that enhance total control and ease automation of the most

complex purification workflows. Multivariable scouting allows numerous

parameters to be evaluated within a method while also maximizing

sample throughput. Bio-Rad Laboratories Inc., bio-rad.com/NGC

DISTEK, INC.Distek, a manufacturer of

laboratory testing instruments

for the pharmaceutical

and biotechnology industry, has added a dual impeller single-use

bioreactor (SUB) system to its BIOne portfolio. The new SUB increases

mixing efficiency within the bioreactor, resulting in an increased mass

transfer coefficient while maintaining the same rate of agitation.

Distek, Inc., 121 North Center Drive, North Brunswick, NJ 08902,

tel: 732.422.7585, [email protected], www.distekinc.com

DELIVERING CONFIDENCE IN QUANTITATIVE MICROBIOLOGYBIOBALL is a small water-soluble

ball containing a precise number

of microorganisms delivering

unprecedented accuracy for quantitative

microbiological quality control. BIOBALL

is easy to use and requires no preparation or pre-incubation and is an

accredited reference material under ISO Guide 34 standards.

www.bioball.com, bioMérieux, Inc., www.biomerieux-usa.com





http://www.distekinc.com

http://www.bioball.com

http://www.biomerieux-usa.com

http://www.bio-rad.com/


Ask the Expert

Contin. on page 45 Fa

na

tic S

tud

io/G

ett

y I

ma

ge

s

A good working relationship between sponsor and

contractor will become invaluable when an OOS occurs.

Q. I’m responsible for quality at a small, vir-

tual startup company and am working on

documentation to contract out our product testing.

What information is there regarding quality agree-

ments and laboratory investigations?

A. The best place to start is to take a criti-

cal look at existing guidance documents

and regulations that govern quality agreements

and out-of-specification (OOS) investigations.

The basic philosophy when establishing any qual-

ity agreement is to understand that the contract

provider and contract giver are partners and their

behaviors reflect on each other.

The 21 Code of Federal Regulations (CFR) 200.10(b)

confirms this concept by stating: “The Food and

Drug Administration is aware that many manufac-

turers of pharmaceutical products utilize extramu-

ral independent contract facilities, such as testing

laboratories, contract packers or labelers, and custom

grinders, and regards extramural facilities as an

extension of the manufacturer’s own facility” (1).

FDA’s Contract Manufacturing Arrangements for Drugs:

Quality Agreements. Section B, Elements of a Quality

Agreement, Part e. Laboratory controls, states that

a quality agreement should include: “Designation

of responsibility for investigating deviations, dis-

crepancies, failures, out-of-specification results, and

out-of-trend results in the laboratory, and for sharing

reports of such investigations” (2). This confirms

that the responsibility for OOS investigations is

shared and communication between the contract

giver and contract provider is critical. The European

Union also addresses the need for a relationship

between you and your outsourced laboratory in

EudraLex: “The Contract should describe clearly who

undertakes each step of the outsourced activity, e.g.

knowledge management, technology transfer, sup-

ply chain, subcontracting, quality and purchasing of

materials, testing and releasing materials, undertak-

ing production and quality controls (including in-

process controls, sampling and analysis)” (3).

These regulations establish the need for qual-

ity agreements that cover laboratory activities but

don’t define what needs to be in an OOS procedure.

The EU addresses the need to investigate OOSs in

their GMPs. EudraLex Part 1, Section 6.35 states,

“Out of specification or significant atypical trends

should be investigated. Any confirmed out-of-spec-

ification result, or significant negative trend, affect-

ing product batches released on the market should

be reported to the relevant competent authorities.

The possible impact on batches on the market

should be considered in accordance with Chapter

8 of the GMP Guide and in consultation with the

relevant competent authorities” (4). Part 2 of the

EU GMP guide for APIs states in section 11.15 that:

“Any out-of-specification result obtained should be

investigated and documented according to a proce-

dure. This procedure should require analysis of the

data, assessment of whether a significant problem

exists, allocation of the tasks for corrective actions,

and conclusions. Any re-sampling and/or retesting

after OOS results should be performed according to

a documented procedure” (5).

FDA’s Guidance for Industry, Investigating Out-of-

Specification (OOS) Test Results for Pharmaceutical

Production (6) clearly defines the responsibilities for

the laboratory analyst and supervisor, which should

be reflected in any laboratory OOS procedure. A well-

written standard operating procedure (SOP) on OOSs

should require investigations to be thorough, timely,

unbiased, well documented, and scientifically sound.

Often, the procedure will contain a checklist that

assists in identifying obvious laboratory errors. The

checklist assesses the suitability of analyst qualifi-

cation and training, use of correct procedure and

specification, the calibration and performance of

the equipment, correct preparation of test solutions

and dilutions, use of proper reagents and standards,

calculations, etc. A thorough checklist and analyst

documentation are critical in identifying true labora-

tory error. The SOP should also discuss the sample

retesting requirements when a true laboratory error

is determined to be the cause of the OOS.

Quality Agreements and Out-of-Specification Investigations Susan Schniepp is executive

vice-president, Post-approval Pharmaceuticals and distinguished

fellow at Regulatory Compliance Associates.

n ScScSSchhhnhnhniiieieiepppppp iiiiisss exexexececec tutututiiiviviveee




https://www.labvantage.com/

https://www.labvantage.com/your-lab-type/pharma-biotech/

CREATING BIOLOGIC TREATMENTS IS SCIENCE. ORCHESTRATING FASTER DEVELOPMENT IS ART.

us + 1 888 SOLUTION (765-8846) EU 00800 8855 6178 catalent.com/onebio © 2019 Catalent Pharma Solutions. All rights reserved

Introducing our latest masterpiece, OneBioSM Suite, which integrates development through complete clinical and commercial supply to simplify, accelerate and de-risk your biologic development.

With our deepest expertise and advanced technologies, we help you deliver better biologic therapies to patients, faster. Catalent, where science meets art.


http://www.catalent.com/index.php

https://biologics.catalent.com/solutions/onebio-integrated-suite/

Volume 32 Number 6 BioPharm - nanoform.com · BioPharma Services Development SGS Life Science...

Documents

Transcript of Volume 32 Number 6 BioPharm - nanoform.com · BioPharma Services Development SGS Life Science...